Phospholipid gel compositions for drug delivery and methods of treating conditions using same

ABSTRACT

The present invention relates to pharmaceutical compositions in the form of a gel for controlled- or sustained-release of a pharmaceutically active agent and to methods for treating or preventing a condition in an animal by administering to an animal in need thereof the pharmaceutical compositions. One particular type of condition for which the pharmaceutical compositions are useful is a microbial infection, e.g., of the skin, ear, or eye, especially for veterinary applications.

1. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.11/019,218 filed 23 Dec. 2004, which is a continuation-in-part ofapplication Ser. No. 10/874,532 filed 24 Jun. 2004, the contents ofwhich are incorporated herein by reference.

2. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

3. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable.

4. BACKGROUND OF THE INVENTION 4.1 Field of the Invention

The present invention relates to pharmaceutical compositions in the formof a gel for controlled- or sustained-release of a pharmaceuticallyactive agent and to methods for treating or preventing a condition in ananimal by administering to an animal in need thereof the pharmaceuticalcompositions. The pharmaceutical compositions are suitable for oral,topical, otic, and ophthalmic applications. One particular type ofcondition for which the pharmaceutical compositions are useful is amicrobial infection, e.g., of the skin, ear, or eye, especially forveterinary applications.

4.2 Description of Related Art

It is often desirable to administer drugs using controlled- orsustained-release formulations that can maintain at least a minimumtherapeutic level, for example, a blood level, of the drug over extendedperiods of time. These controlled- or sustained-release formulationsreduce the frequency of dosing, for enhanced convenience and compliance,and also reduce the severity and frequency of side effects. For example,by maintaining substantially constant blood levels and avoiding bloodlevel fluctuations of the drug, such as are associated with conventionalimmediate release formulations that are administered several times aday, controlled- or sustained-release formulations can provide a bettertherapeutic profile than is obtainable with conventional immediaterelease formulations.

Known methods for controlled- or sustained-drug release includeimplanted devices, such as osmotic pumps, and drug dispersed in abiocompatible polymer matrix, which can be implanted, administeredorally, or injected. Examples of biocompatible polymers used in suchapplications include poly(lactic acid) and poly(lactic acid-co-glycolicacid). The polymer typically undergoes slow hydrolysis in vivo tocontinually release the entrapped drug over time. The polymerdegradation products are non-toxic and absorbed or metabolized by thebody. For example, when the biocompatible polymer is poly(lactic acid)or poly(lactic acid-co-glycolic acid), the degradation products are theparent acids, lactic acid and glycolic acid, which are absorbed by thebody.

U.S. Pat. No. 5,110,809 to Wang et al. discloses a stable anhydrous gelformulations for topical antifungal use containing an imidazole, asteroid, a co-solvent system comprising monohydric and dihydricalcohols, and a hydroxyalkylcellulose gellant.

International Publication No. WO 00/09117 discloses topicalpharmaceutical compositions containing nimesulfide, a non-steroidalanti-inflammatory agent having poor solubility in water.

U.S. Pat. No. 6,214,339 to Pellico discloses a treatment for otitisexterna in cats and dogs that comprises administering a substantiallynon-aqueous, di-enzymatic therapeutic composition, in a liquid or gelfluid carrier. An illustrative composition contains glucose, glucoseoxidase, potassium iodide, and lactoperoxidase in a fluid mixture ofglycerol and propylene glycol.

Eurasian Patent No. EA 0002978 B1 claims in the primary independentclaim a process for preparing a phospholipid suspension.

U.S. patent application No. US 2004/0220264 discloses compositions,methods of making the compositions, and uses of compositions thatinclude a molecular complex between an acidic pharmaceutical drug and afunctional substance. The functional substance can be an alkaline aminoacid, an amino acid amide, an amino acid ester, or a related amino acid.The compositions are allegedly useful for delivering the drug intocutaneous tissue.

U.S. patent application No. US 2004/0197408 discloses formulations of adiblock copolymer having a hydrophobic block and hydrophilic block, anadditive selected from an amino acid, and an oligopeptide. Theformulations, when admixed with water, form drug delivery vehicles inmicellar form.

There remains a need in the art, however, for drug-containingpharmaceutical compositions, especially drug-containing pharmaceuticalcompositions suitable for oral, topical, otic, and ophthalmicapplications, that provide controlled- and/or sustained-release of thedrug contained therein.

Citation of any reference in Section 1 of this application is not to beconstrued that such reference is prior art to the present application.

5. SUMMARY OF THE INVENTION

These and other features and advantages of the present invention willbecome apparent from the remainder of the disclosure, in particular thefollowing detailed description of the preferred embodiments, all ofwhich illustrate by way of example the principles of the invention.

The invention relates to pharmaceutical compositions that providesustained- or controlled-release of a pharmaceutically active compound.

In one embodiment, the pharmaceutical compositions comprise (i) aphospholipid or sphingomyelin; (ii) a polar aprotic organic solvent;(iii) a polar protic organic solvent; and (iv) a pharmaceutically activeagent, wherein the pharmaceutical composition is in the form of a gel.

In one embodiment, the pharmaceutical compositions comprise (i) aphospholipid or sphingomyelin, (ii) a solvent of selected from the groupconsisting of propylene glycol substantially free of other organicsolvents and glycerol formal substantially free of other organicsolvents, and (iii) a pharmaceutically active agent, wherein thepharmaceutical composition is in the form of a gel. In one embodiment,the solvent is glycerol formal substantially free of other organicsolvents. In one embodiment, the solvent is propylene glycolsubstantially free of other organic solvents.

The invention further relates to a method of treating a condition in ananimal comprising administering to an animal in need thereof apharmaceutical composition of the invention.

6. BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable.

7. DETAILED DESCRIPTION OF THE INVENTION

The invention relates to pharmaceutical compositions for controlled- orsustained-release of a pharmaceutically active agent. In one embodiment,the pharmaceutical compositions comprise (i) a phospholipid orspingomyelin, (ii) a first organic solvent, (iii) a second organicsolvent, and (iv) a therapeutically effective amount of apharmaceutically active agent in relative amounts sufficient to causeformation of a gel.

In another embodiment, the pharmaceutical compositions comprise (i) aphospholipid or sphingomyelin, a solvent of selected from the groupconsisting of propylene glycol substantially free of other organicsolvents and glycerol formal substantially free of other organicsolvents, and (iii) a therapeutically effective amount of apharmaceutically active agent in relative amounts sufficient to causeformation of a gel.

The invention further relates a method of treating or preventing acondition in an animal. The method comprises administering to an animalin need thereof a therapeutically effective amount of a pharmaceuticallyactive agent by orally, topically, otically, and/or ophthalmicallyadministering a pharmaceutical composition of the invention.

7.1 Definitions

As used herein, the term “gel” means a material having an averageviscosity of at least about 1,000 centipoise (“cP”), preferably at leastabout 2,000 cP, more preferably at least about 5,000 cP, even morepreferably at least about 7,500 cP, and most preferably at least about10,000 cP but less than about 100,000 cP, preferably less than about75,000 cP at 20° C. Typically, a gel exhibits quiescent and/or dynamicinteraction between its components, e.g., in the form of associationcomplexes, which are generally reversible by application of force (e.g.,shear) and/or temperature to achieve flow.

As used herein, the term “phospholipid” means a compound having thegeneral formula:

wherein

-   -   R₁ is —OH or —O⁻;    -   R₂ is:        -   (i) —H, or        -   (ii) a C₂-C₃₆ saturated or unsaturated, linear or branched            acyl group;    -   R₃ is:        -   (i) —H,        -   (ii) a C₂-C₃₆ saturated or unsaturated, linear or branched            acyl group; or        -   (iii) —C═C—R₉ wherein R₉ is a C₁-C₂₂ saturated or            unsaturated, linear or branched hydrocarbon group,            optionally substituted with one or more nitrogen containing            groups;    -   and at least one of R₂ or R₃ is not —H;    -   R₄ is:        -   (i) —H;        -   (i) —(CH₂)_(n)—R₅,            -   wherein R₅ is —N(R₆)(R₇) or —N⁺(R₆)(R₇)(R₈),            -   R₆, R₇, and R₈ are each independently —H, C₁-C₃ alkyl                group, or R₆ and R₇ are connected to form a 5- or                6-membered heterocyclic ring with the nitrogen, and            -   n is an integer ranging from 1 to 4, preferably 2;

-   -   -   wherein each R₁₀ is independently —H or —P(O)(OH)₂; or        -   (v) —CH₂CH(OH)CH₂(OH).

As used herein, the term “saturated or unsaturated, linear or branchedC₂-C₃₆ acyl group” means a group of formula —O—C(O)—R, wherein R is aC₁-C₃₅ hydrocarbon group that can be saturated or unsaturated, linear orbranched.

As used herein, the term “spingomyelin” means a compound having thegeneral formula:

wherein

R₁ is —OH or —O⁻;

R₄ is:

-   -   (i) —H; or    -   (i) —(CH₂)_(n)—R₅,        -   wherein R₅ is —N(R₆)(R₇) or —N⁺(R₆)(R₇)(R₈),        -   R₆, R₇, and R₈ are each independently —H, C₁-C₃ alkyl, or R₆            and R₇ are connected to form a 5- or 6-membered heterocyclic            ring with the nitrogen, and        -   n is an interger ranging from 1 to 4, preferably 2; and

R₁₁ is a C₁-C₂₂ saturated or unsaturated, linear or branched hydrocarbongroup optionally substituted with one or more nitrogen containinggroups.

As used herein, the term “fatty acid” means a carboxylic acid of formulaR—C(O)OH, wherein R is C₆-C₂₂ linear or branched, saturated orunsaturated, hydrocarbon group. Representative fatty acids include, butare not limited to, caproic acid, caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid, stearic acid, palmic acid,palmitoleic acid, oleic acid, linoleic acid, and linolenic acid.

As used herein, the term “organic solvent” means any organic compound,or a mixture of organic compounds, that is a fluid at or above about 20°C., preferably at or above about 10° C., more preferably at or aboveabout 0° C., most preferably at or above about −10° C. Typical organicsolvents have a molecular weight of not more than about 500 g/mol andpreferably not more than 100 g/mol. When organic solvents areadministered to an animal, it is preferred that the organic solvents arecompounds that do not significantly induce undue adverse effects such asexcessive toxicity, irritation, or allergic response commensurate with areasonable benefit/risk ratio (i.e., “pharmaceutically acceptableorganic solvents”).

As used herein, the term “polar aprotic organic solvent” means anorganic solvent that has a dielectric constant greater than about 20,preferably greater than about 30, and more preferably greater than about50, and does not include an OH functional group.

As used herein, the term “polar protic organic solvent” means an organicsolvent that has a dielectric constant greater than about 20, preferablygreater than about 30, and more preferably greater than about 50, andincludes an —OH functional group.

As used herein, the term “pharmaceutically active agent” means acompound that causes a pharmacological effect in an animal. Typically,the pharmacological effect is treating or preventing a condition in ananimal. A pharmaceutically active agent can advantageously include adrug in its biologically active form, a pro-drug in a form such that thebiologically active drug form is created in vivo in the animal, a drugmetabolite, or a pharmaceutically acceptable salt or ester of abiologically active drug.

The term “animal,” as used herein, includes, but is not limited to,humans, canines, felines, equines, bovines, ovines, porcines,amphibians, reptiles, and avians. Representative animals include, butare not limited to a cow, a horse, a sheep, a pig, an ungulate, achimpanzee, a monkey, a baboon, a chicken, a turkey, a mouse, a rabbit,a rat, a guinea pig, a dog, a cat, and a human. In one embodiment, theanimal is a mammal. In one embodiment, the animal is a human. In oneembodiment, the animal is a canine, a feline, an equine, a bovine, anovine, or a porcine.

The term “condition,” as used herein, means an interruption, cessation,or disorder of a bodily function, system, or organ, and includesdiseases, defects, and disorders. Representative conditions include, butare not limited to, infections such as bacterial, viral, fungal, yeast,and parasitic infections; diseases such as cancer; inflammation;diabetes; and organ failure.

The terms “effective amount” and “therapeutically effective amount,” asused herein, mean an amount sufficient for treating or preventing orpreventing a condition in an animal.

The phrases “treating,” “treatment of,” and the like, include theamelioration or cessation of a specified condition.

The phrases “preventing,” “prevention of,” and the like, include theavoidance of the onset of a condition.

The phrase “pharmaceutically acceptable salt,” as used herein, is a saltformed from an acid and a basic nitrogen group of a pharmaceuticallyactive agent. Illustrative salts include, but are not limited, tosulfate; citrate, acetate; oxalate; chloride; bromide; iodide; nitrate;bisulfate; phosphate; acid phosphate; isonicotinate; lactate;salicylate; acid citrate; tartrate; oleate; tannate; pantothenate;bitartrate; ascorbate; succinate; maleate; gentisinate; fumarate;gluconate; glucaronate; saccharate; formate; benzoate; glutamate;methanesulfonate; ethanesulfonate; benzenesulfonate; p-toluenesulfonate;pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)); and saltsof fatty acids such as caproate, laurate, myristate, palmitate,stearate, oleate, linoleate, and linolenate salts. The phrase“pharmaceutically acceptable salt” also refers to a salt prepared from apharmaceutically active agent having an acidic functional group, such asa carboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N,-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

The phrase “substantially free of,” as used herein, means less thanabout 5 percent by weight, preferably less than about 2 percent byweight, more preferably less than about 1 percent by weight, even morepreferably less than about 0.5 percent by weight, and most preferablyless than about 0.2 percent by weight. For example, the phrase“propylene glycol (or glycerol formal) substantially free of otherorganic solvents” means that the amount of other organic solvents in thepropylene glycol (or glycerol formal) is less than about 5 percent byweight, preferably less than about 2 percent by weight, more preferablyless than about 1 percent by weight, even more preferably less thanabout 0.5 percent by weight, and most preferably less than about 0.2percent by weight of the combined amount of the propylene glycol (orglycerol formal)and the other organic solvents.

4.2 The Phospholipid

Any pharmaceutically acceptable phospholipid can be used in thepharmaceutical compositions of the invention.

Representative, pharmaceutically acceptable phospholipids include, butare not limited to:

phosphatidic acids of general formula:

wherein R₁, R₂, and R₃ are defined above. Suitable phosphatidic acidssuitable for use in the compositions and methods of the inventioninclude, but are not limited to, the1-acyl-2-acyl-sn-glycero-3-phosphates and the1,2-diacyl-sn-glycero-3-phosphates commercially available from AvantiPolar Lipids Inc. of Alabaster, Ala.

phosphatidylethanolamines of general formula

wherein R₁, R₂, and R₃ are defined above. Suitablephosphatidylethanolamines suitable for use in the compositions andmethods of the invention include, but are not limited to, the1-acyl-2-acyl-sn-glycero-3-phosphoethanolamines and the1,2-diacyl-sn-glycero-3-phosphoethanolamines commercially available fromAvanti Polar Lipids Inc. of Alabaster, Ala.

phosphatidylcholines of general formula

wherein R₁, R₂, and R₃ are defined above. Suitable phosphatidylcholinessuitable for use in the compositions and methods of the inventioninclude, but are not limited to, the1-acyl-2-acyl-sn-glycero-3-phosphocholines, the1,2-diacyl-sn-glycero-3-phosphoethanolamines (saturated series), and the1,2-diacyl-sn-glycero-3-phosphoethanolamines (unsaturated series),commercially available from Avanti Polar Lipids Inc. of Alabaster, Ala.and Phospholipon®-50PG, Phospholipon®-53MCT, Phospholipon®-75SA,Phospholipon®-80, Phospholipon®-90NG, Phospholipon®-90H, andPhospholipon®-100H, commercially available from Phospholipid GmbH ofCologne, Germany. In one embodiment, the phospholipid isPhospholipon®-90H.

phosphatidylserines of general formula

wherein R₁, R₂, and R₃ are defined above. Suitable phosphatidylserinessuitable for use in the compositions and methods of the inventioninclude, but are not limited to, the1-acyl-2-acyl-sn-glycero-3-[phospho-L-serine]s and the1,2-diacyl-sn-glycero-3-[phospho-L-serine]s commercially available fromAvanti Polar Lipids Inc. of Alabaster, Ala.

plasmalogens of general formula

wherein R₁ and R₂ are defined above and R₃ is-C═C—R₉, wherein R₉ isdefined above. Suitable plasmalogens suitable for use in thecompositions and methods of the invention include, but are not limitedto, C16(Plasm)-12:0 NBD PC, C16(Plasm)-18:1 PC, C16(Plasm)-20:4 PC,C16(Plasm)-22:6 PC, C16(Plasm)-18:1 PC, C16(Plasm)-20:4 PE, andC16(Plasm)-22:6 PE, commercially available from Avanti Polar Lipids Inc.of Alabaster, Ala.

phosphatidylglycerols of general formula

wherein R₁, R₂, and R₃ are defined above. Suitable phosphatidylglycerolssuitable for use in the compositions and methods of the inventioninclude, but are not limited to, the1-acyl-2-acyl-sn-glycero-3-[phospho-rac-(1-glycerol)]s and the1,2-diacyl-sn-glycero-3-[ phospho-rac-(1-glycerol)]s, commerciallyavailable from Avanti Polar Lipids Inc. of Alabaster, Ala.

phosphatidylinositols of general formula

wherein R₁, R₂, R₃, and R₁₀ are defined above. Suitablephosphatidylinositols suitable for use in the compositions and methodsof the invention include, but are not limited to, phosphatidylinositol,phosphatidylinositol-4-phosphate, andphosphatidylinositol-4,5-bisphosphate, commercially available fromAvanti Polar Lipids Inc. of Alabaster, Ala.

The amount of phospholipid in the pharmaceutical composition typicallyranges from about 0.1 percent to 10 percent by weight of thepharmaceutical composition.

In one embodiment, the amount of phospholipid in the pharmaceuticalcomposition ranges from about 0.5 percent to 7 percent by weight of thepharmaceutical composition.

In one embodiment, the amount of phospholipid in the pharmaceuticalcomposition ranges from about 1 percent to 4 percent by weight of thepharmaceutical composition.

In one embodiment, the amount of phospholipid in the pharmaceuticalcomposition ranges from about 2 percent to 4 percent by weight of thepharmaceutical composition.

In one embodiment, the amount of phospholipid in the pharmaceuticalcomposition is greater than about 1 percent by weight of thepharmaceutical composition.

In one embodiment, the amount of phospholipid in the pharmaceuticalcomposition is greater than about 2 percent by weight of thepharmaceutical composition.

Typically, the greater the concentration of the phospholipid in thepharmaceutical composition the higher the viscosity of thepharmaceutical composition. Accordingly, it is possible to vary theviscosity of the pharmaceutical composition by varying the amount of thephospholipid present in the pharmaceutical composition.

One of ordinary skill in the art will recognize, however, that theamount of phospholipid present in the pharmaceutical compositions of theinvention can vary widely depending on the organic solvents present, thepharmaceutically active agent present, and/or other additionalcomponents present in the pharmaceutical composition.

The phospholipids are commercially available or can be obtained bymethods well known to those skilled in the art. Representative methodsfor obtaining phospholipids are described in Sandra Pesch et al.,Properties of Unusual Phospholipids Bearing Acetylenic Fatty Acids,Tettrahedron, vol. 15, no. 43, 14,627-14634 (1997); Sepp D. Kohlwein,Phospholipid Synthesis, Sorting, Subcellular Traffic—The Yeast Approach,Trends in Cell Biology, vol. 6, 260-266 (1996), Serguei V. Vinogradov,Synthesis of Phospholipids—Oligodeoxyribonucleotide Conjugates, Tett.Lett., vol. 36, no. 14, 2493-2496 (1995), and references cited therein.

4.3 The Sphingomyelin

Any pharmaceutically acceptable sphingomyelin can be used in thepharmaceutical compositions of the invention.

In one embodiment, the sphingomyelin is

wherein R₁₁ is a C₁-C₂₄ linear, saturated or unsaturated hydrocarbon andR₄ is —CH₂CH₂N(CH₃)₃ ⁺. In another embodiment, R₁₁ is a C₈-C₂₄ linear,saturated or unsaturated hydrocarbon and R₄ is —CH₂CH₂N(CH₃)₃ ⁺. Inanother embodiment, R₁₁ is a C₁₆-C₂₄ linear, saturated or unsaturatedhydrocarbon and R₄ is —CH₂CH₂N(CH₃)₃ ⁺.

Suitable sphingomyelins include, but are not limited to,C2-Sphingomyelin, C6-Sphingomyelin, C18-Sphingomyelin,C6-NBD-Sphingomyelin, and C12-NBD Sphingomyelin, commercially availablefrom Avant Polar Lipids Inc. of Alabaster, Ala.

4.4 The Pharmaceutically Active Agent

Any pharmaceutically active agent that is compatible with thephospholipid or sphingomyelin and the polar aprotic organic solvent andpolar protic organic solvent or that is compatible with the phospholipidor sphingomyelin and the propylene glycol substantially free of otherorganic solvents or glycerol formal substantially free of other organicsolvents can be used in the pharmaceutical compositions according to theinvention.

In one embodiment, the pharmaceutically active agent is present as apharmaceutically acceptable salt of the pharmaceutically active agent.

In one embodiment, the pharmaceutically active agent is a zwitterion.

In one embodiment, the pharmaceutically active agent is a basiccompound.

In one embodiment, the pharmaceutically active agent is an acidiccompound.

In one embodiment, the pharmaceutically active agent is a neutralcompound.

The amount of pharmaceutically active agent in the pharmaceuticalcompositions typically ranges from about 0.01 to 30 percent by weight ofthe pharmaceutical composition.

In one embodiment, the pharmaceutically active agent in thepharmaceutical compositions ranges from about 0.01 to 25 percent byweight of the pharmaceutical composition.

In one embodiment, the pharmaceutically active agent in thepharmaceutical compositions ranges from about 0.01 to 20 percent byweight of the pharmaceutical composition.

In one embodiment, the pharmaceutically active agent in thepharmaceutical compositions ranges from about 0.01 to 15 percent byweight of the pharmaceutical composition.

The amount of pharmaceutically active agent in the pharmaceuticalcompositions typically ranges from about 0.01 to 10 percent by weight ofthe pharmaceutical composition.

In one embodiment, the pharmaceutically active agent in thepharmaceutical compositions ranges from about 0.05 to 7.5 percent byweight of the pharmaceutical composition.

In one embodiment, the amount of pharmaceutically active agent in thepharmaceutical composition is from about 0.05 to 5 percent by weight ofthe pharmaceutical composition.

In one embodiment, the amount of pharmaceutically active agent in thepharmaceutical composition is from about 0.1 to 3 percent by weight ofthe pharmaceutical composition.

In one embodiment, the amount of pharmaceutically active agent in thepharmaceutical composition is from about 0.1 to 2 percent by weight ofthe pharmaceutical composition.

In one embodiment, the amount of pharmaceutically active agent in thepharmaceutical composition is from about 0.1 to 1 percent by weight ofthe pharmaceutical composition.

One of ordinary skill in the art will recognize, however, that theamount of pharmaceutically active agent in the pharmaceuticalcompositions according to the invention can vary widely depending on thepharmaceutically active agent and any other components present in thepharmaceutical composition.

Examples of pharmaceutically active agents useful in the composition andmethods of the invention include, but are not limited to, α-adrenergicagonists, β-adrenergic agonists, α-adrenergic blockers, β-adrenergicblockers, aldose reductase inhibitors, anabolics, analgesics (narcoticand non-narcotic), androgens, anesthetics, anorexics, anthelmintics(e.g., cestode, nematode, onchocerca, schistosoma, and the like),anti-allergics, anti-ameboics, anti-yeast agents, anti-androgens,anti-anginals, anti-arrhythmics, anti-arteriosclerotics,anti-arthritics, antibiotics and other antibacterials,anti-cholinergics, anti-convulsants, anti-depressants, anti-diabeticsagents, anti-diarrheals, anti-diuretics, anti-estrogens, antifungals,anti-glaucomas, anti-gonadotropins, anti-gout agents, anti-histaminics,anti-hyperlipoproteinemics, anti-hypertensives, anti-hyperthyroidagents, anti-hypertrophy agents, anti-hypotensives, anti-hypothyroidagents, antiinflammatories, anti-malarials, antimicrobials,anti-migraine agents, anti-nausea agents, anti-neoplastics,antioxidants, antiparasitic agents, anti-parkinsonian agents,anti-pheochromocytoma agents, anti-pneumocytis agents, antiproliferativeagents, anti-protozoals (e.g., leishmania, trichomonas, trypansoma, andthe like), anti-pruritic agents, anti-psoratic agents, anti-psychoticagents, anti-pyretics, anti-rheumatics, anti ricketts agents,anti-seborrheic agents, antiseptics, anti-spasmodic agents,anti-thrombotic agents, antitussives, anti-ulcer agents, anti-urolithicagents, anti-venins, antivirals, anxiolytics, benzodiazepineantagonists, bronchodilators, calcium channel blockers, calciumregulators, cardiotonics, chelating agents, chemotherapeutics,cholecystokinin antagonists, cholelitholytic agents, choleretics,cholinergics, cholinesterase inhibitors, cholinesterase reactivators,central nervous system stimulants and agents, decongestants, diuretics,dopamine receptor agonists, drugs for treating or preventing pain,ectoparasiticides, enzymes, enzyme inducers, estrogens, gastricsecretion inhibitors, glucocorticoids, gonad-stimulating principles,gonadotropic hormones, growth hormones, growth hormone releasingfactors, growth stimulants, hemolytics, heparin agonists,hepatoprotectants, hypnotics, immune system boosters, immunomodulators,immunosuppressants, lactation stimulating hormones, LH-RH stimulatingagonists, lipotropics, lupus erythmatosus suppressants, mineralcorticoids, miotics, monoamine oxidase inhibitors, mucolytics, musclerelaxants, narcotic antagonists, neuroprotectives, neotropics, ovarianhormones, oxytocics, pepsin inhibitors, peristaltic stimulators,progestrogens, prolactin inhibitors, protoglandins, prostoglandinanalogs, protease inhibitors, respiratory stimulants, sclerosing agents,sedatives, steroids, thrombolytics, thyrotropic hormones, transdermalpenetration enhancers, uricosurics, vasoconstrictors, vasodilators(e.g., cerebral, coronary, peropheral, and the like), vasoprotectants,vitamins, vitamin source extracts, vulneraries (including, but notlimited to, those listed in U.S. Pat. No. 5,719,197, the entiredisclosure of which is incorporated herein by reference), andcombinations thereof. Other additionally or alternately acceptablepharmaceutically active agents can be found, e.g., in U.S. Pat. No.6,221,383, the entire disclosure of which is incorporated herein byreference.

In one embodiment, the pharmaceutically active agent comprises anantibacterial agent.

In one embodiment, the pharmaceutically active agent comprises anantifungal agent.

In one embodiment, the pharmaceutically active agent comprises anantiparasitic agent.

In one embodiment, the pharmaceutically active agent comprises ananti-yeast agent.

In one embodiment, the pharmaceutically active agent comprises anantiviral agent.

In one embodiment, the pharmaceutically active agent comprises ahormone.

In one embodiment, the pharmaceutically active agent comprises aantiinflammatory agent.

In one embodiment, the pharmaceutically active agent comprises asteroid.

Examples of useful antibacterial agents include, but are not limited to,β-lactam antibiotics such as penicillins, amoxicillin, ampicillin, andcephalosporins; macrolide antibiotics such as oleandomycin anderythromycin; tetracyclines such as tetracycline, oxytetracycline, andchlortetracycline; procaine penicillin G; quinolones such asenrofloxacin, nalidixic acid, and norfloxacin; sulfonamides;chloramphenicol; florfenicol; thiamphenicol, aminoglycosides such astobramycin, streptomycin, kanamycin, azithromycin, and gentamicin;nucleoside antibiotics such as polyoxin B; actinorhodine; bacitracin;candicidin A; ceftiofor; clindamycin; cycloheximide; cycloserine;fosfomycin; griseofulvin; metronidazole; monensin; novobiocin; rifampin;streptothricin; tetranactin; tilmicosin; tylosin; actinomycin D;adriamycin; bleomycin B2; glycolipids such as moenomycin A; mitomycin C;nojirimycin; valinomycin; and vancomycin; (See, e.g., Bradford P. Smith,Large Animal Internal Medicine, 2nd edn., Mosby, St. Louis, 1996, p.644, and S. Birchard and R. Sherding, Saunders Manual of Small AnimalPractice, W. B. Saunders Company, Philadelphia, 1994, p. 739).

Examples of useful antifungal agents include, but are not limited to,terbinafine amphotericin B, ketaconazole, clotrimazole, miconazole,5-fluorocytosine, enilconazole, itraconazole, thiabendazole, and iodides(See, e.g., Bradford P. Smith, Large Animal Internal Medicine, 2nd edn.,Mosby, St. Louis, 1996, p. 576, and S. Birchard and R. Sherding,Saunders Manual of Small Animal Practice, W.B. Saunders Company,Philadelphia, 1994, p. 576).

Examples of useful antiviral agents include, but are not limited to,interferon (See, e.g., Bradford P. Smith, Large Animal InternalMedicine, 2nd edn., Mosby, St. Louis, 1996, p. 646).

Examples of useful antiparasitic agents include, but are not limited to,benzimidazoles, such as thiabendazole, fenbendazole, mebendazole,nitazoxanide (NTZ), oxfendazole, oxibendazole, albendazole,parbendazole, and febantel; tetrahydropyridines such as moranteltartrate/pyrantel pamoate; levamisole, organophosphates such as haloxon,coumaphos, trichlorfon, and dichlorvos; piperazine salts; ivermectin;and phenothiazine (See, e.g., Bradford P. Smith, Large Animal InternalMedicine, 2nd edn., Mosby, St. Louis, 1996, p. 1688).

Examples of useful antiinflammatory agents include, but are not limitedto, steroids such as betamethazone; corticosteroids such asdexamethasone; antihistamines; and non-steroidal antiinflammatory drugssuch as aspirin, flunixin meglumine, phenylbutazone, diclofenac, andibuprofin (See, e.g., Bradford P. Smith, Large Animal Internal Medicine,2nd edn., Mosby, St. Louis, 1996, p. 645).

Examples of useful anti-yeast agents include, but are not limited to,aminoglycosides such as tobramycin, streptomycin, kanamycin, andgentamicin.

In one embodiment, the pharmaceutically active agent comprisesgentamicin.

In one embodiment, the pharmaceutically active agent comprisesazithromycin.

In one embodiment, the pharmaceutically active agent comprisestobramycin.

In one embodiment, the pharmaceutically active agent comprisestobramycin decanoic acid salt.

In one embodiment, the pharmaceutically active agent comprisestobramycin oleic acid salt.

In one embodiment, the pharmaceutically active agent comprisestobramycin acetic acid salt.

In one embodiment, the pharmaceutically active agent comprisesterbinafine.

In one embodiment, the pharmaceutically active agent comprisesterbinafine decanoic acid salt.

In one embodiment, the pharmaceutically active agent comprisesterbinafine oleic acid salt.

In one embodiment, the pharmaceutically active agent comprisesterbinafine acetic acid salt.

In one embodiment, the pharmaceutically active agent comprisesbetamethazone.

In one embodiment, the pharmaceutically active agent comprisesflorfenicol.

In one embodiment, the pharmaceutically active agent comprisesthiamphenicol.

In one embodiment, the pharmaceutically active agent comprisesclotrimazole.

In one embodiment, the pharmaceutically active agent comprisestilmicosin.

In one embodiment, the pharmaceutically active agent comprises atetracycline compound.

In one embodiment, the pharmaceutically active agent comprisesketoconazole.

In one embodiment, the pharmaceutically active agent comprisesdiclofenac.

In one embodiment, the pharmaceutically active agent comprises flunixin.

In one embodiments, there can be multiple pharmaceutically active agentsin a single pharmaceutical composition.

In one embodiment, the pharmaceutically active agent comprises thecombination of an antibacterial agent, an antifungal agent, and asteroid.

Effective amounts of these pharmaceutically active agents are known tothose skilled in the art. It is well within the skilled artisan'spurview to determine each pharmaceutically active agent's optimaleffective-amount range.

In one embodiment of the invention, where multiple pharmaceuticallyactive agents are administered to an animal, the effective amount ofeach pharmaceutically active agent is less than its effective amountwould be were the other pharmaceutically active agent(s) notadministered. In this case, without being bound by theory, it isbelieved that multiple pharmaceutically active agents can be chosen toact synergistically to treat or prevent a condition (e.g., a bacterialinfection).

In one embodiment, the pharmaceutically active agent comprises acombination of tobramycin, terbinafine, and betamethazone.

In one embodiment, the pharmaceutically active agent comprises acombination of tobramycin decanoic acid salt, terbinafine decanoic acidsalt, and betamethazone.

In one embodiment, the pharmaceutically active agent has an amine moietyand is present in the pharmaceutical composition of the invention as afatty acid salt (“FAS”) by converting the amine moiety to an ammoniumcation whose counterion is a fatty acid moiety such as those describedin International Publication No. WO 03/034988 A2, the entire disclosureof which is incorporated herein in its entirety.

Without being bound to theory, it is believed that a FAS of apharmaceutically active agent provides additional sustained- orcontrolled-release of the pharmaceutically active agent (as reflected inmore steady blood levels as a function of time). Without wishing to bebound by theory, it is believed that the additional sustained- orcontrolled-release of the pharmaceutically active agent obtained whenusing a FAS of a pharmaceutically active agent is because the FAS of apharmaceutically active agent is less soluble in water than thepharmaceutically active agent itself or other non-fatty acid salt of thepharmaceutically active agent and, accordingly, is absorbed by theanimal more slowly.

In one embodiment, the FAS salt of the pharmaceutically active agent isa salt of a C₆-C₁₈ carboxylic acid.

In one embodiment, the FAS salt of the pharmaceutically active agent isa salt of a C₈-C₁₈ carboxylic acid.

In one embodiment, the FAS salt of the pharmaceutically active agent isa salt of a C₁₀-C₁₈ carboxylic acid.

In one embodiment, the FAS salt of the pharmaceutically active agent isa salt of a linear unsaturated fatty acid.

In one embodiment, the FAS salt of the pharmaceutically active agent isa salt of a linear saturated fatty acid.

4.5 Pharmaceutical Compositions 4.5.1 Pharmaceutical CompositionsComprising (i) a Phospholipid or Spingomyelin, (ii) a First OrganicSolvent, (iii) a Second Organic Solvent, and (iv) a TherapeuticallyEffective Amount of a Pharmaceutically Active Agent

Any pharmaceutically active agent described above can be used in thepharmaceutical compositions.

Any phospholipid or sphingomyelin described above can be used in thepharmaceutical compositions.

4.5.1.1 The First Organic Solvent and Second Organic Solvent

Any pharmaceutically acceptable organic solvents can be used in thepharmaceutical compositions of the invention. The first organic solventand the second organic solvent, however, must be miscible.

Suitable organic solvents can include small amounts of impurities.Typically, the organic solvents have a purity of greater than 95 percentby weight, preferably greater than 97 percent by weight, more preferablygreater than 98 percent by weight, and most preferably greater than 99percent by weight.

In one embodiment, the organic solvents are designated as GRAS(“generally recognized as safe”) by the FDA for use or consumption byanimals.

In another embodiment, the organic solvents are designated as GRAS bythe FDA for use or consumption by humans.

In one embodiment, the first organic solvent is a polar aprotic solventand the second organic solvent is a polar protic solvent.

Representative polar aprotic solvents useful in the compositions andmethods of the invention include, but are not limited to, propylenecarbonate, dimethyl sulfoxide (DMSO), dimethyl acetamide (DMA), dimethylformamide (DMF), triacetin, and N-methyl-2-pyrrolidone (NMP).

Representative polar protic solvents useful in the compositions andmethods of the invention include, but are not limited to, glycerolformal and diols, such as propylene glycol and 1,4-butane diol.

When the first organic solvent is a polar aprotic solvent and the secondorganic solvent is a polar protic solvent, the ratio of the firstorganic solvent to the second organic solvent can ranges from about90:10 to 10:90. In one embodiment, the ratio of the first organicsolvent to the second organic solvent ranges from about 80:20 to 20:80.In one embodiment, the ratio of the first organic solvent to the secondorganic solvent ranges from about 70:30 to 30:70. In one embodiment, theratio of the first organic solvent to the second organic solvent rangesfrom about 60:40 to 40:60. In one embodiment, the ratio of the firstorganic solvent to the second organic solvent is about 50:50.

In one embodiment, the first organic solvent and the second organicsolvent are each substantially free of water. Organic solvents that aresubstantially free of water are advantageous since they are notconducive to bacterial growth. Accordingly, it is typically notnecessary to include a preservative in pharmaceutical compositions thatare substantially free of water. However, in some embodiments, thenon-aqueous pharmaceutical composition of the invention can contain apreservative.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is glycerol formal.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is propylene glycol.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is glycerol formal glycol or propylene glycoland the ratio of the first organic solvent to the second organic solventranges from about 80:20 to about 20:80.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is glycerol formal or propylene glycol andthe ratio of the first organic solvent to the second organic solventranges from about 75:25 to about 25:75.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is glycerol formal or propylene glycol andthe ratio of the first organic solvent to the second organic solventranges from about 60:40 to about 40:60.

In one embodiment, the first organic solvent is propylene carbonate andthe second organic solvent is glycerol formal or propylene glycol andthe ratio of the first organic solvent to the second organic solventranges from about 50:50.

The total amount of organic solvent (i.e., the first organic solvent andthe second organic solvent) in the pharmaceutical composition typicallyranges from about 20 to about 99 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the total amount of organic solvent in thepharmaceutical composition is from about 35 to about 90 percent byweight of the pharmaceutical composition.

In one embodiment, the amount of organic solvent in the pharmaceuticalcomposition is at least about 35 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the amount of organic solvent in the pharmaceuticalcomposition is at least about 50 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the amount of organic solvent in the pharmaceuticalcomposition is at least about 75 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the amount of organic solvent in the pharmaceuticalcomposition is at least about 85 percent by weight of the pharmaceuticalcomposition.

4.5.1.2 Representative Pharmaceutical Formulations

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, and the phospholipid is

wherein R₂ and R₃ each are a stearoyl group or a palmitoyl group and theratio of total stearoyl groups to palmitoyl groups is about 85:15 and R₁is O⁻(Phospholipon®90H, commercially available from Phospholipid GmbH ofCologne, Germany).

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the ratio of the propylene carbonate to theglycerol formal ranges from about 60:40 to 40:60.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the ratio of the propylene carbonate to theglycerol formal is about 50:50.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the phospholipid is presentin an amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the phospholipid is present in an amount ofabout 1 to 4 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the phospholipid is presentin an amount of about 3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the phospholipid is present in an amount ofabout 3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound is at leastone of an antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound is at least one of an antibacterial agent, an antifungal agent,or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compound is atleast one of an antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound is at least one ofan antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound is at least one of an antibacterialagent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound is at least one ofan antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound is at least one of an antibacterialagent, an antifungal agent, or a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprises anantibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises an antibacterial agent, an antifungal agent, and asteroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises an antibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprises anantibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises an antibacterial agent, anantifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesantibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises antibacterial agent, anantifungal agent, and a steroid.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof, terbinafine ora pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof, terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises tobramycin or a pharmaceutically acceptable salt thereof,terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof, terbinafine ora pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof, terbinafine or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof, terbinafine ora pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof, terbinafine or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, terbinafine or a pharmaceutically acceptablesalt thereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, and betamethasone or a pharmaceuticallyacceptable ester thereof in an amount of about 0.05 to 0.3 percent byweight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon®90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises tobramycin or a pharmaceutically acceptable salt thereof in anamount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.05 to 0.3 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition, terbinafineor a pharmaceutically acceptable salt thereof in an amount of about 1percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises tobramycin or a pharmaceutically acceptable salt thereof in anamount of about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition, terbinafineor a pharmaceutically acceptable salt thereof in an amount of about 1percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition, terbinafineor a pharmaceutically acceptable salt thereof in an amount of about 1percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises tobramycin or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester. thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof, terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises florfenicol or a pharmaceutically acceptable ester thereof,terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof, terbinafine or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof, terbinafine or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, terbinafine or a pharmaceutically acceptablesalt thereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, and betamethasone or a pharmaceuticallyacceptable ester thereof in an amount of about 0.05 to 0.3 percent byweight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises florfenicol or a pharmaceutically acceptable ester thereof inan amount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.05 to 0.3 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises florfenicol or a pharmaceutically acceptable ester thereof inan amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof in an amount of about 1percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises florfenicol or apharmaceutically acceptable ester thereof in an amount of about 1percent by weight of the pharmaceutical composition, terbinafine or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof, clotrimazoleor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof, clotrimazole or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises gentamicin or a pharmaceutically acceptable salt thereof,clotrimazole or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof, clotrimazoleor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof, clotrimazole or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof, clotrimazoleor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof, clotrimazole or apharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, clotrimazole or a pharmaceuticallyacceptable salt thereof in an amount of about 1 to 3 percent by weightof the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.05 to0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises gentamicin or a pharmaceutically acceptable salt thereof in anamount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, clotrimazole or a pharmaceutically acceptable salt thereofin an amount of about 1 to 3 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.05 to 0.3 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, clotrimazole or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, clotrimazole or apharmaceutically acceptable salt thereof in an amount of about 1 to 3percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about0.05 to 0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, clotrimazole or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, and the pharmaceutically active compoundcomprises gentamicin or a pharmaceutically acceptable salt thereof in anamount of about 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about1 to 4 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, clotrimazole or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal ranges from about 60:40 to 40:60, the phospholipid is present inan amount of about 3 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the first organic solvent is propylene carbonate, thesecond organic solvent is glycerol formal, the phospholipid isPhospholipon® 90H, the ratio of the propylene carbonate to the glycerolformal is about 50:50, the phospholipid is present in an amount of about3 percent by weight of the pharmaceutical composition, and thepharmaceutically active compound comprises gentamicin or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, clotrimazole or apharmaceutically acceptable salt thereof in an amount of about 1 percentby weight of the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In each pharmaceutical composition described in this section, theglycerol formal can be replaced with propylene glycol.

4.5.2 Pharmaceutical Compositions Comprising (i) a Phospholipid orSphingomyelin, a Solvent of Selected from the Group Consisting ofPropylene Glycol Substantially Free of Other Organic Solvents andGlycerol Formal Substantially Free of Other Organic Solvents, and (iii)a Pharmaceutically Active Agent

Any pharmaceutically active agent described above that is compatiblewith the phospholipid and the propylene glycol or glycerol formal can beused in the pharmaceutical compositions.

Any phospholipid or sphingomyelin described above can be used in thepharmaceutical compositions.

4.5.2.1 The Propylene Glycol or Glycerol Formal

Propylene glycol is an organic solvent represented by the formula:CH₃—CH₂(OH)—CH₂—OH or HO—CH₂—CH₂—CH₂—OH.

In one embodiment, the proplene glycol is 1,2-propylene glycol. Inanother embodiment, the propylene glycol is 1,3-propylene glycol. In oneembodiment, the proplene glycol is a mixture of 1,2-propylene glycol and1,3-propylene glycol.

Glycerol formal is an organic solvent of formula C₄H₈O₃ and exists as amixture of 5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane in aratio of about 60:40. Although the solvent glycerol formal consists oftwo chemical compounds, the two chemical compounds being in a specificratio of about 60:40, it is typically considered a “solvent” rather thana mixture of compounds. This is because the 5-hydroxy-1,3-dioxane and4-hydroxymethyl-1,3-dioxolane are in equilibrium with each other.Accordingly, the term glycerol formal (i.e., a mixture of5-hydroxy-1,3-dioxane and 4-hydroxymethyl-1,3-dioxolane in a ratio ofabout 60:40), as used herein, is an organic solvent substantially freeof other organic solvents.

The propylene glycol and the glycerol formal can include small amountsof impurities. Typically, the propylene glycol and the glycerol formalhas a purity of greater than 95 percent by weight, preferably greaterthan 98 percent by weight, more preferably greater than 99 percent byweight. The solvent, especially glycerol formal, can include astabilizer. Typically, the stabilizer is present in an amount of 0.5weight percent or less, preferably an amount of 0.25 weight percent orless, and most preferably an amount of 0.5 weight percent or less. Forexample, commercially available glycerol formal typical containsethylenediaminetetraacetate (EDTA), thiodipropionic acid, and propylgallate as stabilizers.

In one embodiment, the propylene glycol or the glycerol formal issubstantially free of water. Propylene glycol or glycerol formalsubstantially free of water is advantageous since they are not conduciveto bacterial growth. Accordingly, it is typically not necessary toinclude a preservative in pharmaceutical compositions that aresubstantially free of water. However, in some embodiments, thenon-aqueous pharmaceutical composition of the invention can contain apreservative.

The amount of the propylene glycol or the glycerol formal in thepharmaceutical composition typically ranges from about 20 to about 99percent by weight of the pharmaceutical composition.

In one embodiment, the amount of the propylene glycol or the glycerolformal in the pharmaceutical composition ranges from about 35 to about90 percent by weight of the pharmaceutical composition.

In one embodiment, the amount of the propylene glycol or the glycerolformal in the pharmaceutical composition is at least about 35 percent byweight of the pharmaceutical composition.

In one embodiment, the amount of the propylene glycol or the glycerolformal in the pharmaceutical composition is at least about 50 percent byweight of the pharmaceutical composition.

In one embodiment, the amount of the propylene glycol or the glycerolformal in the pharmaceutical composition is at least about 75 percent byweight of the pharmaceutical composition.

In one embodiment, the amount of the propylene glycol or the glycerolformal in the pharmaceutical composition is at least about 85 percent byweight of the pharmaceutical composition.

4.5.2.2 Representative Pharmaceutical Formulations

In one embodiment, the solvent is propylene glycol or glycerol formaland the phospholipid is Phospholipon® 90H (commercially available fromPhospholipid GmbH of Cologne, Germany).

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the phospholipid is presentin an amount of about 1 to 4 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the phospholipid is presentin an amount of about 1 to 2 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound is at least one of an antibacterial agent, an antifungal agent,or a steroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound is at least one ofan antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound is at least one ofan antibacterial agent, an antifungal agent, or a steroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises terbinafine.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesterbinafine.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesterbinafine.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises gentamicin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises tobramycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises azithromycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises florfenicol.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises an antibacterial agent, an antifungal agent, and asteroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprises anantibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprises anantibacterial agent, an antifungal agent, and a steroid.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof, terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof, terbinafine ora pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof, terbinafine ora pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, terbinafine or a pharmaceutically acceptablesalt thereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, and betamethasone or a pharmaceuticallyacceptable ester thereof in an amount of about 0.05 to 0.3 percent byweight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises tobramycin or a pharmaceutically acceptable saltthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition, terbinafineor a pharmaceutically acceptable salt thereof in an amount of about 1percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisestobramycin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition, terbinafineor a pharmaceutically acceptable salt thereof in an amount of about 1percent by weight of the pharmaceutical composition, and betamethasoneor a pharmaceutically acceptable ester thereof in an amount of about 0.1percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises azithromycin or a pharmaceutically acceptable saltthereof, terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises azithromycin or a pharmaceutically acceptable saltthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, terbinafine or a pharmaceutically acceptablesalt thereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, and betamethasone or a pharmaceuticallyacceptable ester thereof in an amount of about 0.05 to 0.3 percent byweight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises azithromycin or a pharmaceutically acceptable saltthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesazithromycin or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof, terbinafine or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof, terbinafineor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, terbinafine or a pharmaceutically acceptablesalt thereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, and betamethasone or a pharmaceuticallyacceptable ester thereof in an amount of about 0.05 to 0.3 percent byweight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises florfenicol or a pharmaceutically acceptable esterthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, terbinafine or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesflorfenicol or a pharmaceutically acceptable ester thereof in an amountof about 1 percent by weight of the pharmaceutical composition,terbinafine or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof, clotrimazole or a pharmaceutically acceptable salt thereof, andbetamethasone or a pharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof, clotrimazoleor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof, clotrimazoleor a pharmaceutically acceptable salt thereof, and betamethasone or apharmaceutically acceptable ester thereof.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof in an amount of about 1 to 3 percent by weight of thepharmaceutical composition, clotrimazole or a pharmaceuticallyacceptable salt thereof in an amount of about 1 to 3 percent by weightof the pharmaceutical composition, and betamethasone or apharmaceutically acceptable ester thereof in an amount of about 0.05 to0.3 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 to 3 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 to 3 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.05 to 0.3 percent by weight of the pharmaceuticalcomposition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, and the pharmaceutically activecompound comprises gentamicin or a pharmaceutically acceptable saltthereof in an amount of about 1 percent by weight of the pharmaceuticalcomposition, clotrimazole or a pharmaceutically acceptable salt thereofin an amount of about 1 percent by weight of the pharmaceuticalcomposition, and betamethasone or a pharmaceutically acceptable esterthereof in an amount of about 0.1 percent by weight of thepharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 4 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

In one embodiment, the solvent is propylene glycol or glycerol formal,the phospholipid is Phospholipon® 90H, the phospholipid is present in anamount of about 1 to 2 percent by weight of the pharmaceuticalcomposition, and the pharmaceutically active compound comprisesgentamicin or a pharmaceutically acceptable salt thereof in an amount ofabout 1 percent by weight of the pharmaceutical composition,clotrimazole or a pharmaceutically acceptable salt thereof in an amountof about 1 percent by weight of the pharmaceutical composition, andbetamethasone or a pharmaceutically acceptable ester thereof in anamount of about 0.1 percent by weight of the pharmaceutical composition.

4.5.3 General Features of the Pharmaceutical Compositions

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 1,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 2,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 5,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 10,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 15,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 20,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofgreater than about 25,000 cP at 20° C.

Typically, the pharmaceutical composition has a viscosity of less thanabout 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity ofless than about 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 1,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 2,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 5,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 10,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 20,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 25,000 cP to 100,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 1,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 2,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 5,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 10,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 20,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 25,000 cP to 75,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 2,000 cP to 25,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 5,000 cP to 25,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 2,000 cP to 18,000 cP at 20° C.

In one embodiment, the pharmaceutical composition has a viscosity thatranges from about 5,000 cP to 18,000 cP at 20° C.

Viscosity is determined using a Brookfield DV-E viscometer (commerciallyavailable from Brookfield of Middleboro, Mass.).

4.5.4 Optional Additives

The present pharmaceutical compositions can optionally comprise asuitable amount of a pharmaceutically acceptable preservative, ifdesired, so as to provide additional protection against microbialgrowth.

Examples of preservatives useful in the pharmaceutical compositions ofthe invention include, but are not limited to, potassium sorbate,methylparaben, propylparaben, benzoic acid and its salts, other estersof parahydroxybenzoic acid such as butylparaben, alcohols such as ethylor benzyl alcohol, phenolic compounds such as phenol, or quartemarycompounds such as benzalkonium chlorides (e.g., benzethonium chloride).

In one embodiment, the pharmaceutical compositions of the invention canoptionally contain a suitable amount of a pharmaceutically acceptablepolymer. The polymer further increases the viscosity of thepharmaceutical composition. Many of the pharmaceutical compositions ofthe invention lose their gel properties at temperatures greater thanabout 40° C. By including a polymer in the pharmaceutical compositions,the pharmaceutical compositions maintain their gel properties at highertemperatures.

Suitable polymers for use in the compositions and methods of theinvention include, but are not limited to, hydroxypropylcellulose,hydoxypropylmethylcellulose (HPMC), chitosan, polyacrylic acid, andpolymethacrylic acid.

In one embodiment, the polymer is HPMC.

In one embodiment, the polymer is hydroxypropylcellulose,

In one embodiment, the polymer is polyacrylic acid. In one embodiment,the polyacrylic acid is a crosslinked polyacrylic acid such as Carbomer®(commercially available from Carbomer, Inc. of Westborough, Mass.).

In one embodiment, the polymer is polymethacrylic acid.

Typically, the polymer is present in an amount ranging from greater than0 to 10 percent by weight of the pharmaceutical composition.

In one embodiment, the polymer is present in an amount ranging fromabout 0.1 to 10 percent by weight of the pharmaceutical composition.

In one embodiment, the polymer is present in an amount ranging fromabout 1 to 7.5 percent by weight of the pharmaceutical composition.

In one embodiment, the polymer is present in an amount ranging fromabout 1.5 to 5 percent by weight of the pharmaceutical composition.

In one embodiment, the polymer is present in an amount ranging fromabout 2 to 4 percent by weight of the pharmaceutical composition.

The components of the pharmaceutical composition (the polymer, thesolvents, and the pharmaceutically active agent, as well as any otheroptional components) are preferably biocompatible and non-toxic and,over time, are simply absorbed and/or metabolized by the body.

In one embodiment, the pharmaceutical compositions of the invention aresubstantially free of polymers.

In one embodiment, any additional components added to the pharmaceuticalcompositions of the invention are designated as GRAS by the FDA for useor consumption by animals.

In another embodiment, any additional components added to thepharmaceutical compositions of the invention are designated as GRAS bythe FDA for use or consumption by humans.

4.6 Methods of Treating a Condition in an Animal

The pharmaceutical compositions of the invention are useful in humanmedicine and veterinary medicine.

In one embodiment, the method of treating or preventing a condition inan animal comprises administering to the animal in need thereof atherapeutically effective amount of a pharmaceutically active agent byorally administering a pharmaceutical composition of the invention.

In one embodiment, the method of treating or preventing a condition inan animal comprises administering to the animal in need thereof atherapeutically effective amount of a pharmaceutically active agent byotically applying a pharmaceutical composition of the invention.

In one embodiment, the method of treating or preventing a condition inan animal comprises administering to the animal in need thereof atherapeutically effective amount of a pharmaceutically active agent byophthalmically applying a pharmaceutical composition of the invention.

In one embodiment, the method of treating or preventing a condition inan animal comprises administering to the animal in need thereof atherapeutically effective amount of a pharmaceutically active agent bytopically applying a pharmaceutical composition of the invention.

The pharmaceutical compositions of the invention are viscouscompositions. Viscous compositions containing drugs have advantages overless viscous (thinner) liquid formulations for treating or preventingconditions in animals. For example, in topical applications, oticapplications, and ophthalmic applications, especially veterinary uses,thinner liquid formulations are easily washed or swept away from atarget area of delivery than formulations that are more viscous(thicker). For treating conditions such as microbial infections,particularly in non-human animals, the advantages of thickerpharmaceutical compositions include maintaining the pharmaceuticallyactive agent, like antibiotics, in the target area for longer periods oftime.

The pharmaceutical compositions of the invention are particularly usefulin veterinary medicine, especially for otic applications. For example,when treating or preventing otic microbial infections in small animals,such as cats and dogs, the pharmaceutical composition is typicallyadministered in an amount of about 0.5 mL per ear. Larger amounts,however, can be administered for larger animals.

The pharmaceutical compositions of the invention are advantageous inveterinary medicine, especially for otic application, compared tocommercially available pharmaceutical compositions. For example, whentreating or preventing otic microbial infections in animals usingcommercially available pharmaceutical compositions the animal typicallyshakes its head and dislodges the composition from the target infectedarea (and often out of the ear entirely). This occurs readily withcommercially available antibiotic compositions since they have lowerviscosity. However, the pharmaceutical compositions of the invention,having a higher viscosity, are not as easily dislodged, thus renderingthem more effective in delivering the pharmaceutically active agent tothe target infected area and remaining present for extended periods atthe infected area to provide controlled- or sustained-release of thepharmaceutically active agent.

Advantageously, the pharmaceutical compositions of the invention need tobe applied less frequently than commercially available pharmaceuticalcompositions. Often only two doses or a single dose of thepharmaceutical compositions of the invention are effective at treatingor preventing otic microbial infections in animals. In contrast,commercially available pharmaceutical compositions typically requiremany more doses. For example, OTOMAX® (commercially available fromSchering-Plough Animal Health of Union N.J.) requires 2 doses per dayfor 7 days.

Further, the pharmaceutical compositions of the invention are typicallymore lipophilic than aqueous or semi-aqueous formulations. Without beingbound by theory, it is believed that the increased lipophilicity of thepharmaceutical compositions of the invention renders them more effectivethan aqueous or semi-aqueous formulations, particularly for treating orpreventing ear infections in an animal, because the pharmaceuticalcompositions of the invention are more compatible with the highlylipophilic environment of the animal's ear.

The pharmaceutical compositions of the invention also adhere well to theskin and, accordingly, are useful for topical application.

The pharmaceutical compositions of the invention can also beadministered orally. To administer the pharmaceutical compositionsorally, the pharmaceutical composition can, for example, be encapsulatedin a capsule, such as a hard gelatin capsule or a soft gelatin capsule,and the capsule orally administered to the animal. Suitable capsules foruse in the invention are Shionogi Qualicaps (commercially available fromand Shionogi & Co., Ltd of Osaka, Japan). Oral dosage forms can bedesigned to release the pharmaceutically active compound in the stomachimmediately or almost immediately or to provide sustained release of thepharmaceutically active compound in the stomach. The oral dosage formscan also be designed to release the pharmaceutically active compound inthe intestines immediately or almost immediately or to provide sustainedrelease of the pharmaceutically active compound in the intestines. Todelay the release of the pharmaceutically active compound until thedosage form reaches the intestines, the capsule is coated with anenteric coating. Typically, the enteric coating is a pH sensitivepolymer such as Eudragit® L-100 (commercially available from DeGussa AGof Frankfurt, Germany). The rate of release of the pharmaceuticallyactive compound is varied by varying the amount of phospholipid orsphingomyelin in the pharmaceutical composition and the presence ofpolymers in the pharmaceutical composition.

When administered topically, otically, or opthalmically, thepharmaceutical compositions of the invention can provide controlled- orsustained-release of the pharmaceutically active agent in apharmaceutically effective amount for up to about 15 days and evenlonger.

In one embodiment, the pharmaceutical compositions according to theinvention provide controlled- or sustained-release of thepharmaceutically active agent in a pharmaceutically effective amount forat least about 4 to about 15 days.

In another embodiment, the pharmaceutical compositions according to theinvention provide controlled- or sustained-release of thepharmaceutically active agent in a pharmaceutically effective amount forat least about 4 to about 10 days.

In another embodiment, the pharmaceutical compositions according to theinvention provide controlled- or sustained-release of thepharmaceutically active agent in a pharmaceutically effective amount forat least about 1 week.

In a preferred embodiment, the pharmaceutical compositions of theinvention, by providing controlled- or sustained-release of thepharmaceutically active agent, have reduced toxicity, particularly insmall animals such as cats and dogs. Accordingly, the pharmaceuticalcompositions according to the invention have a better therapeuticprofile that conventional immediate release formulations. Methods thatinvolve administering a pharmaceutically active agent to an animal bytopically, otically, or ophthalmically applying a pharmaceuticalcomposition of the invention permit pharmaceutically active agents to beadministered to animals that could potentially (if administered inpresently available dosage forms) result in toxicity and even death ofthe animal being treated. By advantageously providing controlled- orsustained-release of the pharmaceutically active agents, thepharmaceutical composition of the invention can be administered lessfrequently and therefore also be easier to use, more convenient, andmore cost effective than conventional modes of administeringpharmaceutically active agents.

The amount of the pharmaceutically active agent(s) that is(are)effective in treating or preventing a condition, e.g., a bacterialinfection, can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays can optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed willalso depend on the route of administration, the seriousness of thecondition, and the animal being treated and can be decided according tothe judgment of a practitioner and/or each animal's circumstances.Suitable effective dosage amounts, however, can typically range fromabout 0.1 mg/kg of body weight to about 100 mg/kg of body weight,preferably about 1 mg/kg of body weight to about 50 mg/kg of bodyweight, more preferably from about 2 mg/kg of body weight to about 30mg/kg of body weight, for example from about 5 mg/kg of body weight toabout 100 mg/kg of body weight. The effective dosage amounts describedherein refer to total amounts of all pharmaceutically active agentsadministered; that is, if more than one pharmaceutically active agent isadministered, the effective dosage amounts correspond to the totalamount administered.

Typically, pharmaceutical composition is administered from about 1 timeeach day to about 1 time each week until the condition is abated.

In one embodiment, the pharmaceutical composition is administered onceeach day until the condition is abated.

In one embodiment, the pharmaceutical composition is administered twiceeach day until the condition is abated.

In one embodiment, the pharmaceutical composition is administered onceeach week until the condition is abated.

In one embodiment, the pharmaceutical composition is administered twiceeach week until the condition is abated.

In one embodiment, the pharmaceutical composition is administered aboutevery 12 hours until the condition is abated.

In one embodiment, the pharmaceutical composition is administered asingle time. In many cases the pharmaceutical compositions are effectiveat treating or preventing a condition in an animal.

In one embodiment, the pharmaceutical composition is administered dailyfor 1 week.

In one embodiment, the pharmaceutical composition is administered aboutevery 7 days for 4 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 7 days for 3 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 7 days for 2 weeks.

In one embodiment, the pharmaceutical composition is administered twiceabout 24 hours apart.

In one embodiment, the pharmaceutical composition is administered twiceabout 48 hours apart.

In one embodiment, the pharmaceutical composition is administered aboutevery 24 hours for about 4 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 12 hours for about 4 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 24 hours for about 2 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 12 hours for about 2 weeks.

In one embodiment, the pharmaceutical composition is administered aboutevery 24 hours for about 1 week.

In one embodiment, the pharmaceutical composition is administered aboutevery 12 hours for about 1 week.

In another embodiment, an effective dosage amount is administered dailyuntil the condition is abated. The total dose may optionally be dividedinto daily doses and/or into about 2 to 4 individual doses.

In one embodiment, the condition is a bacterial infection.

Representative bacterial infections that can be treated using thepharmaceutical compositions of the invention include, but are notlimited to, bacterial infections caused by bacteria of the genusPasteurella, Haemophilus, Fusobacterium, Moraxella, Bacteroides,Aeromonas, Escherichia, Enterobacter, Klebsiella, Salmonella, Shigella,Serratia, Ureaplasma, Chlamydia, Actinobacillus, Streptococcus,Edwardsiella, Staphylococcus, Enterococcus, Bordetella, Proteus,Mycoplasma, or Mannheimia.

Representative bacterial infections that can be treated using thepharmaceutically active agents of the invention include, but are notlimited to, bacterial infections caused by Pasteurella haemolytica,Pasteurella multocida, Pasteurella haemolytica, Haemophilus somnus,Actinobacillus pleuropneumoniae, Actinomyces pyogenes, Pseudomonasaeruginosa, Klebsiella Pneumonia, Escherichia Faecalis, EscherichiaColi, Staphylococcus Aureaus, Streptococcus Pyogenes, Bacillus Subtilis,Streptococcus spp., Staphylococcus spp., Moraxella spp., Salmonellaspp., Bacteroides spp., Peptococcus indolicus, Fusobacterium spp.,Mycoplasma bovis, Mycoplasma dispar, Ureaplasma spp., Chlamydia spp.,Mycoplasma mycoides, Mycoplasma ovipneumonia, Haemophilus influenzae,Klebsiella salmonella, Shigella, Proteus Enterobacter, Serratia, andBordetella bronchoseptica.

In one embodiment, the condition is a fungal infection.

In one embodiment, the condition is a yeast infection.

Without being bound by theory, it is believed that the pharmaceuticalcompositions of the invention wherein the pharmaceutical composition isin the form of a gel containing the pharmaceutically active agent(s)allows for higher loading than can be attained with liposomalformulations (where the maximum loading is believed to be only about 1percent by weight of the liposome-containing composition). Indeed,pharmaceutical composition containing homogenously distributedpharmaceutically active agents in as much as about 5 percent by weightof the pharmaceutical compositions, and even more, are routinelypossible using the compositions of the invention. Indeed, pharmaceuticalcomposition containing homogenously distributed pharmaceutically activeagents in as much as about 25 percent by weight of the pharmaceuticalcompositions are possible. The pharmaceutical compositions of theinvention are preferably substantially free of liposomes. In oneembodiment, the pharmaceutical compositions of the invention are free ofliposomes.

In one embodiment, the animal is a non-human animal.

In another embodiment, the animal is a human.

In another embodiment, the animal is a cat.

In another embodiment, the animal is a dog.

In another embodiment, the animal is a cow.

In another embodiment, the animal is a pig.

In another embodiment, the animal is a sheep.

In another embodiment, the animal is a horse.

4.7 Preparing Pharmaceutical Compositions

The pharmaceutical compositions of the invention comprising (i) aphospholipid or sphingomyelin; (ii) a first organic solvent; (iii) asecond organic solvent; and (iv) a pharmaceutically active agent, can beprepared, for example, by simply adding the pharmaceutically activeagent(s) to a mixture of the first organic solvent and the secondorganic solvent (“solvent mixture”) (typically about 90% of the amountof the solvent mixture desired in the final pharmaceutical composition)and agitating or stirring the resulting mixture until thepharmaceutically active agent(s) dissolve(s). One or more optionaladditive(s) can simultaneously and/or sequentially be added and themixture agitated or stirred until the optional additive(s) dissolve(s).The phospholipid is then added to the mixture, with agitation orstirring, and optionally with heat to provide a phospholipid mixture.Typically the mixture is heated at a temperature of less than 100° C.,preferably less than 70° C., more preferably less than about 50° C., andmost preferably about 40° C. before the phospholipid is added.Additional solvent mixture is then added to provide the desiredconcentration of the pharmaceutically active agent(s) in thepharmaceutical composition and the phospholipid mixture is allowed tocool to room temperature to provide the pharmaceutical composition.

Similarly the pharmaceutical compositions of the invention comprising(i) a phospholipid or sphingomyelin, a solvent of selected from thegroup consisting of propylene glycol substantially free of other organicsolvents and glycerol formal substantially free of other organicsolvents, and (iii) a pharmaceutically active agent can be prepared, forexample, by simply adding the pharmaceutically active agent(s) to thepropylene glycol or glycerol formal (typically about 90% of the amountof the solvent desired in the final pharmaceutical composition) andagitating or stirring the resulting mixture, optionally with heat, untilthe pharmaceutically active agent(s) dissolve(s). One or more optionaladditive(s) can simultaneously and/or sequentially be added and themixture agitated or stirred until the optional additive(s) dissolve(s).The phospholipid is then added to the mixture, with agitation orstirring, and optionally with heat to provide a phospholipid mixture.Typically the mixture is heated at a temperature of less than 100° C.,preferably less than 70° C., more preferably less than about 50° C., andmost preferably about 40° C. before the phospholipid is added.Additional propylene glycol or glycerol formal is then added to providethe desired concentration of the pharmaceutically active agent(s) in thepharmaceutical composition and the phospholipid mixture is allowed tocool to room temperature to provide the pharmaceutical composition.

One skilled in the art, however, will readily recognize thatmodifications to the above-described methods for preparing thepharmaceutical compositions of the invention are possible, for examplethe order of adding the components to the solvent(s) can be changed.

4.8 Kits

The invention encompasses kits that can simplify the administration of apharmaceutically active agent to an animal. A typical kit of theinvention comprises a unit dosage form of a pharmaceutical compositionaccording to the invention. In one embodiment, the unit dosage form is acontainer (such as a vial, a pouch, a tube, a syringe, or the like),which can advantageously be sterile, containing a pharmaceuticalcomposition of the invention. The kit can further comprise a label orprinted instructions instructing the use of the pharmaceutically activeagent to treat or prevent a condition. In another embodiment, the kitcomprises a unit dosage form of a pharmaceutical composition of theinvention and a dropper, syringe, or other applicator for administeringthe pharmaceutical composition. Typically, the components of the kit,for example, the unit dosage form and instructions, are contained withina suitable packaging material.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES Example 5.1 Phospholipid Pharmaceutical Composition in theForm of a Gel

Tobramycin (2.5 g), terbinafine (2.5 g), decanoic acid (6.34 g),betamethasone acetate (250 mg), and benzethonium chloride (50 mg) weredissolved in 150 mL of stabilized glycerol formal and the resultingmixture heated to about 40° C. with stirring to provide a clearsolution. To the resulting solution was added 37.5 mL of stabilizedglycerol formal and 62.5 mL of propylene carbonate and the resultingsolution heated to about 40° C. with stirring to provide a clearsolution. Phospholipon®-90H (2.5 g) (commercially available fromPhospholipid GmbH of Cologne, Germany) was added to the 40° C. solutionwith stirring to provide a clear solution. Hydroxypropylmethylcellulose(5 g) was then added to the 40° C. solution with stirring to provide aclear solution. The solution was allowed to cool to room temperature toprovide a gel. The resulting gel contains about 1.25% by weight ofPhospholipon®.

The resulting gel contained 1% tobramycin as a decanoic acid salt, 1%terbinafine as a decanoic acid salt, 0.1% betamethasone acetate, and0.02% benzethonium chloride and had a viscosity of 2,346 cP at 20° C.

Example 5.2 Phospholipid Pharmaceutical Composition in the Form of a Gel

Florfenicol (5 g), betamethasone acetate (500 mg), oleic acid (4.8 g),and benzethonium chloride (100 mg) were dissolved in 250 mL of propylenecarbonate and the resulting mixture heated to a temperature of betweenabout 40-45° C. with stirring to provide a clear solution. To theresulting solution was added 284.5 g of stabilized glycerol formal andthe resulting solution heated to about 40° C. with stirring to provide aclear solution. Phospholipon®-90H (5 g) (commercially available fromPhospholipid GmbH of Cologne, Germany) was then added to the 40° C.solution with stirring to provide a clear solution. The solution wasallowed to cool to room temperature overnight to provide a gel. Theresulting gel had a viscosity of 52,300 cP at 20° C.

The following day, 150 mL of the gel was warmed to about 40° C. toprovide a liquid and hydroxypropylmethylcellulose (4.5 g) was added tothe liquid at 40° C. and the resulting mixture allowed to stir at 40° C.for about 15 min. The mixture was then cooled to room temperature toprovide a gel. The resulting gel contains about 2% by weight ofPhospholipon®.

The resulting gel contained 1% florfenicol, 1% terbinafine as an oleicacid salt, 0.1% betamethasone acetate, and 0.02% benzethonium chlorideand had a viscosity of 17,880 cP at 20° C.

Example 5.3 Phospholipid Pharmaceutical Composition in the Form of a Gel

Tobramycin (5 g), terbinafine (5 g), decanoic acid (6.35 g), acetic acid(2.21 g), betamethasone acetate (500 mg), and benzethonium chloride (100mg) were dissolved in 375 mL of stabilized glycerol formal and 90 mL ofpropylene carbonate were added to the solution. The resulting mixturewas heated to about 40° C. and Phospholipon®-90H (5 g) (commerciallyavailable from Phospholipid GmbH of Cologne, Germany) was added withstirring to provide a clear solution. Hydroxypropylmethylcellulose (15g) was then slowly added to the 40° C. solution with stirring. Thesolution was stirred for 15 min. and then allowed to cool to roomtemperature to provide a gel. The resulting gel contains about 2.5% byweight of Phospholipon® and about 3% by weight ofhydroxypropylmethylcellulose.

The resulting gel contained 1% tobramycin as a mixture of the decanoicacid salt and acetic acid salt, 1% terbinafine as a mixture of thedecanoic acid salt and acetic acid salt, 0.1% betamethasone acetate, and0.02% benzethonium chloride and had a viscosity of 3,650 cP at 20° C.

Example 5.4 Phospholipid Pharmaceutical Composition in the Form of a Gel

Florfenicol (5 g), betamethasone acetate (500 mg), oleic acid (4.8 g),and benzethonium chloride (100 mg) were dissolved in 250 mL of propylenecarbonate and the resulting mixture heated to a temperature of betweenabout 40-45° C. with stirring to provide a clear solution. To theresulting solution was added 284.5 g of stabilized glycerol formal andthe resulting solution heated to about 40° C. with stirring to provide aclear solution. Phospholipon®-90H (7.5 g) (commercially available fromPhospholipid GmbH of Cologne, Germany) was then added to the 40° C.solution with stirring to provide a clear solution. The solution wasallowed to cool to room temperature overnight to provide a gel. Theresulting gel contains about 3% by weight of Phospholipon®. Theresulting gel contained 1% florfenicol, 1%, 0.1% betamethasone acetate,and 0.02% benzethonium chloride and had a viscosity of 65,300 cP at 20°C.

Example 5.5 Phospholipid Pharmaceutical Composition in the Form of a Gel

Tobramycin (2.5 g), terbinafine (2.5 g), decanoic acid (6.35 g),betamethasone acetate (250 mg), and benzethonium chloride (50 mg) weredissolved in 187.5 mL of stabilized glycerol formal and heated to about40° C. 45 mL of propylene carbonate was added to the solution and thetemperature maintained at about 40° C. Phospholipon®-90H (2.5 g)(commercially available from Phospholipid GmbH of Cologne, Germany) wasthen added to the resulting solution with stirring to provide a clearsolution. Hydroxypropylmethylcellulose (10 g) was then slowly added tothe 40° C. solution with stirring. The solution was stirred for 15 min.and then allowed to cool to room temperature to provide a gel. Theresulting gel contains about 2.5% by weight of Phospholipon® and about4% by weight of hydroxypropylmethylcellulose.

The resulting gel contained 1% tobramycin as the decanoic acid salt, 1%terbinafine as a the decanoic acid salt, 0.1% betamethasone acetate, and0.02% benzethonium chloride and had a viscosity of 17,160 cP at 20° C.

Example 5.6 Phospholipid Pharmaceutical Composition in the Form of a Gel

Florfenicol (10 g), terbinafine (10 g), oleic acid (9.7 g),betamethasone acetate (1 g), and benzethonium chloride (1 g) weredissolved in about 500 mL of glycerol formal and the resulting mixtureheated to about 40° C. with stirring to provide a solution. To theresulting 40° C. solution was added Phospholipon®-90H (10 g)(commercially available from Phospholipid GmbH of Cologne, Germany) andhydroxypropylmethylcellulose (30 g) with stirring to provide a solution.The solution was then filled to a volume of 1000 mL (at 40° C.) withglycerol formal. The total amount of glycerol formal was 898.46 g. Thesolution was allowed to cool to room temperature to provide a gel. Theresulting gel contains about 1% by weight of Phospholipon®, about 1% byweight florfenicol, about 1% by weight terbinafine as a oleic acid salt,about 0.1% by weight betamethasone acetate, and about 0.1% by weightbenzethonium chloride.

Example 5.7 Phospholipid Pharmaceutical Composition in the Form of a Gel

Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g),decanoic acid (6.35 g), acetic acid (2.21 g), and benzethonium chloride(0.5 g) were dissolved in about 300 mL of glycerol formal and theresulting mixture heated to a temperature of about 40° C. with stirringto provide a solution. To the resulting 40° C. solution was addedPhospholipon®-90H (10 g) (commercially available from Phospholipid GmbHof Cologne, Germany) and hydroxypropylmethylcellulose (10 g) withstirring to provide a solution. The solution was then filled to a volumeof 500 mL (at 40° C.) with glycerol formal. The total amount of glycerolformal was 568.66 g. The solution was allowed to cool to roomtemperature to provide a gel. The resulting gel contains about 2% byweight of Phospholipon®, about 1% by weight tobramycin as a mixture ofthe decanoic acid salt and acetic acid salt, about 1% by weightterbinafine as a mixture of the decanoic acid salt and acetic acid salt,about 0.1% betamethasone acetate, and about 0.1% benzethonium chloride.

A similar formulation can be made by replacing the tobramycin withazithromycin (8 g).

Example 5.8 Phospholipid Pharmaceutical Composition in the Form of a Gel

About 300 mL of glycerol formal was heated to about 40° C. and decanoicacid (41.7 g) and tilmicosin (108.2 g, 92.4% purity) was added to theglycerol formal. The resulting mixture was stirred to provide asolution. Phospholipon®-90H (15 g) (commercially available fromPhospholipid GmbH of Cologne, Germany) was added with stirring toprovide a solution. Hydroxypropylmethylcellulose (12 g) was then slowlyadded to the 40° C. solution with stirring. Glycerol formal was thenadded to provide a volume of 500 mL (at 40EC) and the solution allowedto cool to room temperature to provide a gel. The resulting gel containsabout 3% by weight of Phospholipon®, about 2.4% by weight ofhydroxypropylmethylcellulose, and about 20% by weight of tilmicosin as adecanoic acid salt.

A similar formulation can be made by replacing the tilmicosin withazithromycin (100 g).

Example 5.9 Phospholipid Pharmaceutical Composition in the Form of a Gel

Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g),decanoic acid (6.35 g), acetic acid (2.21 g), and benzethonium chloride(0.5 g) were dissolved in about 300 mL of glycerol formal and theresulting mixture heated to a temperature of about 40° C. with stirringto provide a solution. To the resulting 40° C. solution was addedPhospholipon®-90H (10 g) (commercially available from Phospholipid GmbHof Cologne, Germany) with stirring to provide a solution. The solutionwas then filled to a volume of 500 mL (at 40° C.) with glycerol formal.The total amount of glycerol formal was 568.66 g. The solution wasallowed to cool to room temperature to provide a gel. The resulting gelcontains about 2% by weight of Phospholipon®, about 1% by weighttobramycin as a mixture of the decanoic acid salt and acetic acid salt,about 1% by weight terbinafine as a mixture of the decanoic acid saltand acetic acid salt, about 0.1% betamethasone acetate, and about 0.1%benzethonium chloride. This phospholipid pharmaceutical composition inthe form of a gel contains no polymers.

Example 5.10 Phospholipid Pharmaceutical Composition in the Form of aGel

Tobramycin (5 g), terbinafine (5 g), betamethasone acetate (0.5 g),decanoic acid (6.35 g), acetic acid (2.21 g), and benzethonium chloride(0.5 g) were dissolved in about 300 mL of glycerol formal and theresulting mixture heated to a temperature of about 40° C. with stirringto provide a solution. To the resulting 40° C. solution was addedPhospholipon®-90H (10 g) (commercially available from Phospholipid GmbHof Cologne, Germany) with stirring to provide a solution. The solutionwas then filled to a volume of 500 mL (at 40° C.) with glycerol formal.The solution was allowed to cool to room temperature to provide a gel.The resulting gel contains about 2% by weight of Phospholipon®, about 1%by weight tobramycin as a mixture of the decanoic acid salt and aceticacid salt, about 1% by weight terbinafine as a mixture of the decanoicacid salt and acetic acid salt, about 0.1% betamethasone acetate, andabout 0.1% benzethonium chloride.

A similar formulation can be made by replacing the tobramycin withazithromycin (8 g).

Example 5.11 Clinical Study

Several dogs with ear infections were administered the pharmaceuticalcomposition of Example 5.1, 5.2, or 5.3.

The following protocol was followed to evaluate the clinical efficacy ofthe pharmaceutical compositions of the invention.

Dogs with ear infections were examined by a veterinarian on day 0 andeach ear was assigned a clinical score based on the following signsrelated to otis externa: pain, erythema, exudate, swelling, odor andulceration. The following scale was used:

Pain 0 = none 1 = mild/moderate: painful on palpation 2 = severe:painful when raise the pinna Erythema 0 = none 1 = mild/moderate: barelyperceptible to obvious redness visible with otoscope 2 = severe: beet orcherry red or erythema extends into pinna Exudate 0 = none 1 =mild/moderate: small amount visible in ear canal 2 = severe: extendingout of ear canal and may be crusted Swelling 0 = none 1 = mild moderate:some oclussion of ear canal 2 = severe: canal completely occluded Odor 0= none 1 = mild/moderate: malodor evident when oinna raised 2 = severe:malodor evident without raising oinna to expose ear canal Uceration 0 =none 1 = mild/moderate: mild abrasions 2 = severe: abrasions that may bebleeding

The score for pain, erythema, exudate, swelling, odor and ulceration wascombined to provide total clinical score ranging from 0 to 12 with 12being the most severe otis externa and 0 being the least severe otisexterna.

On day 0 the dog also received a physical exam, an ear swab was obtainedto submit for a bacterial and yeast culture, and a second ear swab wasobtained to prepare a roll smear to identify bacteria and/or yeast. Thedogs ear was also cleaned with a cleansing solution free ofantimicrobial and anti-inflammatory activity and excess solution wasremoved from the ear. 0.5 mL of the pharmaceutical composition ofExample 5.1, 5.2, or 5.3 was then administered to each infected ear andthe ears massaged to distribute the pharmaceutical composition.

On day 7 ( ) 2 days) a clinical score was again assigned to each earusing the same scale as used on day 0. On day 7 ( ) 2 days) 0.5 mL ofthe same pharmaceutical composition as was administered on day 0 wasagain administered to each infected ear and the ears massaged todistribute the pharmaceutical composition.

On day 14 ( ) 2 days) a clinical score was again assigned to each earusing the same scale as used on day 0.

Various breeds of dogs were used in the study of both sexes, variousbody weights, and physiological states. All dogs were at least 8 weeksold and in general good health. For inclusion in the study the dogs hada minimum total clinical score on day 0 of 6, received no treatment withsystemic or otic antimicrobials or anti-inflammatories within the lastmonth, intact tympanic membranes, visualization of bacteria or yeast onthe roll smear, and no concurrent Otodectes cynotis infections.

The results of the study are provided below in Table I. Dogs in Group Awere treated with the pharmaceutical composition of example 5.1, dogs inGroup B were treated with the pharmaceutical composition of example 5.2,and dogs in Group C were treated with the pharmaceutical composition ofexample 5.3.

TABLE I Score Day 0 Animal Left Day 7 Day 14 No. Ear Right Ear Left EarRight Ear Left Ear Right Ear Group A¹  1 7 7 3 3 1 1  4 3 6 2 2 0 2  710 0 1 0 0 0 10 9 9 4 3 2 0 13 12 12 2 0 1 0 16 2 9 3 4 0 4 19 10 6 3 31 2 22 12 12 6 6 5 5 25 0 12 0 6 4 5 28 10 9 4 4 2 3 Group B²  2 8 8 3 00 0  5 6 8 2 2 2 0  8 10 0 4 0 6 0 11 0 12 0 4 0 1 14 10 10 0 0 0 0 17 87 0 0 0 0 20 0 10 0 2 0 0 23 9 4 4 3 2 0 26 8 7 1 2 1 1 29 7 0 3 0 1 0Group C³  3 0 8 0 6 0 6  6 8 8 2 2 1 0  9 0 8 0 2 0 2 12 10 10 4 4 2 215 0 10 0 0 0 0 18 8 8 8 8 8 8 21 7 6 2 2 0 1 24 0 12 0 1 0 4 27 8 8 2 12 0 30 10 8 1 1 1 0 ¹Dogs in Group A were treated with thepharmaceutical composition of example 5.1. ²Dogs in Group B were treatedwith the pharmaceutical composition of example 5.2. ³Dogs in Group Cwere treated with the pharmaceutical composition of example 5.3.

The data in Table I clearly shows that the pharmaceutical compositionsof the invention are effective at treating otic microbial infections indogs.

Example 5.12 Clinical Study

Several dogs with ear infections were administered the pharmaceuticalcomposition of Example 5.6 or Example 5.7. Dogs treated with thepharmaceutical composition of Example 5.6 were designated as Group A anddogs treated with the pharmaceutical composition of Example 5.7 weredesignated as Group B.

The same protocol as was used in Example 5.10 was used to evaluate theclinical efficacy of the pharmaceutical compositions of the invention.

Dogs with ear infections were examined by a veterinarian on day 0 andeach ear was assigned a clinical score based using the scale describedin Example 5.10. The score for pain, erythema, exudate, swelling, odorand ulceration was combined to provide total clinical score ranging from0 to 12 with 12 being the most severe otis extema and 0 being the leastsevere otis extema.

On day 0 the dog also received a physical exam, a clinical score wasassigned to each ear, an ear swab was obtained to submit for a bacterialand yeast culture (a dacron-tipped swab was inserted into the ear canaland then placed in a Port-A-Cul

transport tube (commercially available from BD (Becton, Dickinson andCompany) of Franklin Lakes, N.J.) for shipment to a reference laboratoryfor culturing, and a second ear swab was obtained to prepare a rollsmear to identify bacteria and/or yeast (a Q-tip was inserted into theear canal and then rolled onto a slide and the slide heat fixed andstained using Diff-Quick (commercially available from IMEB Inc. ofChicago, Ill.). 0.5 mL of the pharmaceutical composition of Example 5.6or Example 5.7 was then administered to each infected ear using a 1 mLsyringe and the ears massaged to distribute the pharmaceuticalcomposition.

On day 7, a clinical score was again assigned to each ear using the samescale as used on day 0 and 0.5 mL of the same pharmaceutical compositionas was administered on day 0 was again administered to each infected earand the ears massaged to distribute the pharmaceutical composition.

On day 14, a clinical score was again assigned to each ear using thesame scale as used on day 0.

Various breeds of dogs were used in the study of both sexes, variousbody weights, and physiological states. All dogs were at least 8 weeksold and in general good health. For inclusion in the study the dogs hada minimum total clinical score on day 0 of 6, received no treatment withsystemic or otic antimicrobials or anti-inflammatories within the lastmonth, had intact tympanic membranes, showed visualization of bacteriaor yeast on the roll smear, and no concurrent Otodectes cynotisinfections.

The results of the study are provided below in Table II. Dogs in Group Awere treated with the pharmaceutical composition of Example 5.6 and dogsin Group B were treated with the pharmaceutical composition of Example5.7. A final clinical score of 2 in each ear was considered an effectivetreatment.

TABLE II Score Day 0 Animal Left Day 7 Day 14 No. Ear Right Ear Left EarRight Ear Left Ear Right Ear Group A¹ ROB01 8 8 2 2 1 1 ROB03 9 9 3 3 00 ROB05 6 9 0 3 0 0 ROB07 6 8 1 2 0 0 ROB09 7 8 2 2 0 0  ROB011 7 7 0 00 0 Group B² ROB02 9 9 3 3 0 0 ROB04 6 6 2 2 0 0 ROB06 10 10 3 3 2 0ROB08 8 8 3 3 6 6  ROB010 7 7 1 1 0 0  ROB012 9 9 3 3 0 0 ¹Dogs in GroupA were treated with the pharmaceutical composition of Example 5.6. ²Dogsin Group B were treated with the pharmaceutical composition of Example5.7.

The data in Table V clearly shows that the otic microbial infection ineach dog of Group A was effectively treated (100%) and that the oticmicrobial infection in each dog of Group B, except for dog ROB08, waseffectively treated (83.3%). Dog ROB08, however, did show improvement.The data in Table V clearly shows that the pharmaceutical compositionsof the invention are effective at treating otic microbial infections indogs.

Example 5.13 Stability of the Pharmaceutical Compositions

Pharmaceutical composition, prepared as described in Example 5.1, 5.2,and 5.3 were incubated at a temperature of about 40° C. or about 70° C.for up to 7 days to monitor the degradation of the pharmaceuticallyactive agents as a function of time and temperature. The concentrationof the pharmaceutically active agents was determined at each time pointby the following procedure:

200 mg of the pharmaceutical composition is weighed into a 100 mLvolumetric flask and the flask is filled to volume with 80:20hexane:ethanol and shaken for about 1 min. The HMPC precipitates. 2 mLof the resulting solution is then filtered through an Acrodisc 25 mmsyringe filter (0.2 :m Ultipore nylon membrane) and 10 :L of thefiltered solution is injected onto a Phenomenex Luna, 5 :m, CN100A, 250mm×4.6 mm, analytical HPLC column. The HPLC is operated at a flow rateof 1 mL/min and eluted with 65% hexane and 35% undenatured 200 proofethanol for 20 min. The HPLC is equipped with a UV detector. Terbinafineand florfenicol are detected at 223 nm and Betamethasone acetate isdetected at 240 nm. Terbinafine has a retention time of about 4.0 min.,betamethasone acetate has a retention time of about 4.4 min., andflorfenicol has a retention time of about 7.1 min.

The results of three such stability tests are provided in Table III-V.

TABLE III Stability of the Pharmaceutical Composition of Example 5.1Betamethasone Terbinafine Tobramycin Acetate Day 40° C. 70° C. 40° C.70° C. 40° C. 70° C. 1 101.2 98.7  nd¹ nd 85.6 81.3 2 101.2 98.2 nd nd84.7 80.1 3 101.5 96.5 nd nd 81.8 81.1 4 101.2 97.4 nd nd 80.0 79.9 597.8 94.7 nd nd 80.9 79.2 6 98.8 94.6 nd nd 80.7 79.5 7 99.1 92.0 nd nd80.6 79.1 ¹nd = not determined

TABLE IV Stability of the Pharmaceutical Composition of Example 5.2Betamethasone Terbinafine Florfenicol Acetate Day 40° C. 70° C. 40° C.70° C. 40° C. 70° C. 1 99.0 101.1 102.7 113.0 100.9 101.0 2 99.2 99.3102.4 105.1 101.1 98.3 3 98.9 97.2 104.9 101.1 101.9 97.6 4 98.6 97.9100.6 99.0 100.2 97.1 5 100.8 92.9 104.4 96.7 99.5 97.1 6 98.7 92.6 97.497.5 100.3 98.4 7 98.5 92.8 104.3 107.2 100.1 97.0

TABLE V Stability of the Pharmaceutical Composition of Example 5.3Betamethasone Terbinafine Tobramycin Acetate Day 40° C. 70° C. 40° C.70° C. 40° C. 70° C. 1 99.8 98.0  nd¹ nd 101.6 89.6 2 99.3 99.1 nd nd99.2 88.0 3 99.8 99.8 nd nd 101.0 88.9 4 98.6 97.1 nd nd 101.3 87.4 598.6 96.5 nd nd 96.2 87.2 6 98.3 96.5 nd nd 93.9 86.9 7 98.9 96.5 nd nd92.3 87.1 ¹nd = not determined

The data in Tables III, IV, and V show that the pharmaceuticalcomposition of Example 5.1, 5.2, and 5.3, respectively, have goodstability.

5.14 Phospholipid Pharmaceutical Composition for Oral Administration

300 mL of stabilized glycerol formal and 50 mL of propylene glycol werecombined and warmed to 40° C. To the resulting solvent mixture was added41.7 g of decanoic acid and the mixture with stirring to provide asolution. Tilmicosin (108.2 g, 92.4% pure) was then added to the 40° C.solution with stirring to provide a solution. Phospholipon®-90H (15 g)(commercially available from Phospholipid GmbH of Cologne, Germany) wasadded to the 40° C. solution with stirring to provide a solution.Hydroxypropylmethylcellulose (12 g) was then added to the 40° C.solution with stirring to provide a solution. The solution was filled toa volume of 500 mL at 40° C. and then allowed to cool to roomtemperature to provide a gel. The resulting gel contains about 3% byweight of Phospholipon®, 2.4% by weight of hydroxypropylmethylcellulose,and 20% by weight of tilmicosin as a decanoic acid salt.

The resulting gel can then be placed in gelatin capsules to provide acapsule containing tilmicosin as a decanoic acid salt.

5.15 Phospholipid Pharmaceutical Composition for Oral Administration

300 mL of stabilized glycerol formal and 75 mL of propylene carbonatewere combined and warmed to 40° C. To the resulting solvent mixture wasadded 41.7 g of decanoic acid and the mixture with stirring to provide asolution. Tilmicosin (108.2 g, 92.4% pure) was then added to the 40° C.solution with stirring to provide a solution. Phospholipon®-90H (15 g)(commercially available from Phospholipid GmbH of Cologne, Germany) wasadded to the 40° C. solution with stirring to provide a solution.Hydroxypropylmethylcellulose (12 g) was then added to the 40° C.solution with stirring to provide a solution. The solution was filled toa volume of 500 mL at 40° C. and then allowed to cool to roomtemperature to provide a gel. The resulting gel contains about 3% byweight of Phospholipon®, 2.4% by weight of hydroxypropylmethylcellulose,and 20% by weight of tilmicosin as a decanoic acid salt.

The resulting gel can then be placed in gelatin capsules to provide acapsule containing tilmicosin as a decanoic acid salt.

5.16 Clinical Study

Tilmicosin was orally administered to a dog using the pharmaceuticalcomposition of Example 5.14. A sufficient amount of the gel of example5.14 was placed in a gelatin capsule to provide a dose of 20 mg/kg tothe dog. The dog was then orally administered the gelatin capsulecontaining the tilmicosin pharmaceutical composition of Example 5.14.Blood was then withdrawn from the dog at various time intervals and theserum concentration of tlmicosin determined by the following procedure:

(i) A C-18 cartridge (commercially available from Waters Corp. ofMilford, Mass.) was connected to a 20 mL syringe and to a singlediaphragm vacuum pump (commercially available from Gast ManufacturingInc. of Benton Harbor, Mich.). The C-18 cartridge was condition bywashing with 10 mL of methanol followed by 10 mL of deionized water at aflow rate of less than 5 mL per min;

(ii) 1 mL of serum was poured into the syringe and eluted through theC-18 cartridge;

(iii) The cartridge was washed with 10 mL of 25% aqueous acetonitrilefollowed by 10 mL of water;

(iv) The cartridge was then dried in a desiccator under high vacuum for10 min;

(v) The cartridge was then eluted into a 2 mL volumetric flask with 5%acetic acid in methanol and the resulting 2 mL sample stored in therefrigerator overnight; and

(vi) The sample was then stirred using a vortex mixer and filtered intoan amber high pressure liquid chromatography HPLC vial using a Pallacrodisk syringe filter (commercially available from Pall Corp. of EastHills, N.Y.) to provide a solution for analysis of tilmicosin by HPLC.

HPLC analysis was performed by injecting 100 :L of the solution on a 25cm×4.6 mm phenomenex sphericlone 5 :m analytical column equipped with aphenomenex phenyl(phenylpropyl) guard column. The HPLC was operated at aflow rate of 1.5 mL/min and eluted using gradient elution according tothe following profile:

Percent Percent Pump C Percent Pump A Pump B (20 mM aqueous Time(Acetonitrile) (Water) Dibutylamine) 0.0 50 50 0 3.0 50 50 0 4.0 15 85 05.0 15 0 85 25.0 25 0 75 25.1 50 50 0 30.0 50 50 0for 30 min. The HPLC was equipped with a UV detector operated at 280 nm.Tilmicosin eluted with a retention time of between 13 and 19 min.

The serum concentration of tilmicosin in the serum as a function of timeis provided in Table VI.

TABLE VI Tilmicosin Concentration in Serum as a Function of TimeTilmicosin Concentration Time (hours) (:g/mL) 6 0.3 12 0.23 24 0.18 480.1

The results show that administering the pharmaceutical composition ofprovides tilmicosin in the blood for the dog for at least 48 h.

Example 5.17 Phospholipid Composition for Topical Administration

A pharmaceutical composition was prepared in substantially the samemanner as the pharmaceutical composition described in Example 5.5 andwith the same components, except that the pharmaceutical compositioncontained 0.1% benzethonium chloride.

Example 5.18 Clinical Study

Several dogs with ear infections were administered the pharmaceuticalcomposition of Example 5.17. The following protocol was followed toevaluate the clinical efficacy of the pharmaceutical composition ofExample 5.17.

Dogs with ear infections were examined by a veterinarian on day 0 andeach ear was assigned a clinical score using the same scale as was usedin Example 5.11. If both ears were infected the right ear was designatedas the study ear. On day 0 a roll smear was obtained by inserting aDacron-tipped swab into the ear canal and then rolling the swab onto aslide followed by heat fixing and staining the slide using DifQuik. Onday 0 a culture of the dogs infected ear was obtained by inserting aDacron tipped swab into the ear canal and then placing the swab in aPort-A-Cul transport tube for shipment to a reference laboratory.

For study inclusion, dogs had to be 8 weeks of age or older, have aminimum clinical score of 6, and have intact tympanic membranes. Inaddition, the presence of either yeast or bacteria on a roll smear wasrequired. Animals were excluded from study enrollment if the clinicalscore was less than 6; if they had been treated with systemic or oticantimicrobials or parenteral or topical anti-inflammatories, includingshort-acting corticosteroids within the last 14 days; if they had beentreated with parenteral or topical long-acting corticosteroids withinthe last 28 days; if they had concurrent Otodectes cynotis infections;or if foreign bodies were found in the ear canal.

Dogs were divided into two groups, Group A and Group B. Dogs in Group Awere administered a single 0.5 mL dose of the pharmaceutical compositionof Example 5.17 in each infected ear on day 0 and dogs in Group B wereadministered a single 1.0 mL dose of the pharmaceutical composition ofExample 5.17 in each infected ear on day 0. The appropriate dose wasplaced in the ear canal with a 1 cc syringe followed by massaging theear.

Various breeds of dogs were used in the study. Tables VII-X describe thebreed, age, gender, and weight of the animals in the study.

TABLE VII Study Population by Breed Breed Group A Group B Total BassettHound 0 1 1 Cocker Spaniel 1 1 2 Collie 0 2 2 Coonhound (Red Tick) 1 0 1Dachshund 0 1 1 Dalmation 0 1 1 English Toy Spaniel 0 1 1 GermanShepherd 0 1 1 Labrador Retriever 1 0 1 Mixed Breed 3 1 4 Shih Tzu 3 0 3Standard Poodle 1 1 2 Total 10 10 20

TABLE VIII Study Population by Age Age Group A Group B Total <1 year 3 36 >1 and ≦5 years 3 3 6 >5 and ≦10 years 3 3 6 >10 years 1 1 2 Total 1010 20

TABLE IX Study Population by Gender Sex Group A Group B Total Female 0 22 Spayed female 2 4 6 Male 3 3 6 Castrated male 5 1 6 Total 10 10 20

TABLE X Study Population by Body Weight Body Weight Group A Group BTotal ≦10 lbs 2 1 3 >10 lbs and ≦25 lbs 2 4 6 >25 lbs and ≦50 lbs 1 01 >50 lbs 5 5 10 Total 10 10 20

On day 7 and day 14 a clinical score was again assigned to the infectedear. The results of the study are provided below in Tables XI.

TABLE XI Clinical Results Score Score Score Dog Group^(a) Day 0 Day 7Day 14 1 A 7 3 4 2 B 7 2 1 3 A 9 2 3 4 B 7 4 2 5 A 7 1 1 6 B 10 4 1 7 A12 No visit 3 8 B 8 2 1 9 A 9 2 0 10 B 9 5 2 11 A 7 0 0 12 B 9 3 0 13 A7 2 1 14 B 8 2 0 15 A 11 6 2 16 B 9 2 1 17 A 12 7 2 18 B 9 2 1 19 A 10 44 20 B 8 FTC^(b) FTC^(b) ^(a)Dogs in Group A were administered a singledose of 0.5 mL of the pharmaceutical composition of Example 5.17 and thedogs of Group B were administered a single dose of 0.5 mL of thepharmaceutical composition of Example 5.17. ^(b)FTC = Failed to completestudy.

A final clinical score of 2 or less was considered a treatment success.The results in Table XI show that 60 percent of the dogs in Group A and100 percent of the dogs in Group B were successfully treated.

Table XII describes the culture results.

TABLE XII Culture Results Dog Group^(a) Bacteria Day 0 Yeast Day 0^(c,d)Bacteria Day 14 Yeast Day 14^(c,d) 1 A Negative Negative NegativeNegative 2 B Negative MZ (2) NA NA 3 A

MZ (4)

MZ (3) 4 B S. intermedius (4) Negative NA NA 5 A Negative MZ (4) NA NA 6B S. intermedius (4) Negative NA NA 7 A

MZ (3) Not done Not done 8 B S. intermedius (4) MZ (3) NA NA 9 ANegative Negative NA NA 10 B Negative Negative NA NA 11 A Negative MZ(4) NA NA 12 B S. intermedius (2) MZ (1) NA NA 13 A Negative MZ (2) NANA 14 B S. intermedius (1) Negative NA NA 15 A Negative MZ (3) NA NA 16B S. intermedius (4) Negative NA NA 17 A S. intermedius (4) MZ (4) NA NA18 B S. intermedius (4) MZ (3) NA NA 19 A S. intermedius Negative Notdone Not done (4), β-hemolytic Streptococcus 20 B S. intermedius (4) MZ(4) FTC^(b) FTC ^(a)Dogs in Group A were administered a single dose of0.5 mL of the pharmaceutical composition of Example 5.17 and the dogs ofGroup B were administered a single dose of 0.5 mL of the pharmaceuticalcomposition of Example 5.17. ^(b)FTC = Failed to complete study. ^(c)MZdenotes Malasezzia pachydermatis *Bold entries indicate treatmentfailures ^(d)Scoring scale: 1 = 1 to 10 colonies; 2 = 11 to 100colonies; 3 = 101 to 1000 colonies; 4 => 1000 colonies.

The results in Table XI and XII clearly show that the pharmaceuticalcompositions of the invention are effective at treating otic microbialinfections in dogs.

5.19: Clinical Study

A male patient bothered with athletes foot his entire life applied asingle dose of the pharmaceutical composition of Example 5.17 to theaffected area of the foot. Five days after a single application, theskin area that the pharmaceutical composition was applied to was smooth,gaining its natural color back, and itch free whereas the surroundingarea was dry, flaky, irritable, and very itchy. The patient reportedthat the pharmaceutical composition of Example 5.17 was more effectivethan commercially available antifungal creams that he had been applyingtwice daily.

5.20: Phospholipid Composition for Topical Administration

Florfenicol (5 g), terbinafine (5 g), oleic acid (4.85 g), betamethasoneacetate (500 mg) and benzthonium chloride (100 mg) were suspended in 250mL (298.4 g) of propylene carbonate in a clean dry 1 liter glass beaker.The mixture was warmed to between 40-45° C. with stirring to provide aclear solution. To the resulting clear solution, maintained at atemperature between 40-45° C., was added 284.5 g of stabilized glycerolwith stirring. To the resulting solution was added 10 g ofPhospholipon®-90H with stirring while maintaining the temperaturebetween 40-45° C. to provide a clear solution. The solution was allowedto cool slowly to room temperature to provide a gel.

Example 5.21 Clinical Study

Several dogs with ear infections were administered the pharmaceuticalcomposition of Example 5.20. The following protocol was followed toevaluate the clinical efficacy of the pharmaceutical composition of theinvention.

Dogs with ear infections were examined by a veterinarian on day 0 andeach ear was assigned a clinical score using the same scale as was usedin Examples 5.11 and 5.18. If both ears were infected the right ear wasdesignated as the study ear. On day 0 a roll smear was obtained byinserting a Dacron-tipped swab into the ear canal and then rolling theswab onto a slide followed by heat fixing and staining the slide usingDifQuik. On day 0 a culture of the dogs infected ear was obtained byinserting a Dacron tipped swab into the ear canal and then placing theswab in a Port-A-Cul transport tube for shipment to a referencelaboratory.

For study inclusion, dogs had to be 8 weeks of age or older, have aminimum clinical score of 6, and have intact tympanic membranes. Inaddition, the presence of either yeast or bacteria on a roll smear wasrequired. Animals were excluded from study enrollment if the clinicalscore was less than 6; if they had been treated with systemic or oticantimicrobials or parenteral or topical anti-inflammatories, includingshort-acting corticosteroids within the last 14 days; if they had beentreated with parenteral or topical long-acting corticosteroids withinthe last 28 days; if they had concurrent Otodectes cynotis infections;or if foreign bodies were found in the ear canal.

Dogs were administered a single 1.0 mL dose of the pharmaceuticalcomposition of Example 5.20 in each infected ear on day 0 using a 1 ccsyringe followed by massaging the ear. Various breeds of dogs were usedin the study. Tables XIII-XVI describe the breed, age, gender, andweight of the animals in the study.

TABLE XIII Study Population by Breed Breed Number Beagle 1 BostonTerrier 1 Brittany Spaniel 1 Cocker Spaniel 3 Dalmation 1 Dandie DinmontTerrier 1 Golden Retriever 1 Labrador Retriever 2 Mixed 1 PortugeseWater Dog 1 Sharpei 3 Shih Tzu 2 Yorkshire Terrier 2 Total 20

TABLE XIV Study Population by Age Age Number <1 year 3 >1 and ≦5 years7 >5 and ≦10 years 2 >10 years 8 Total 20

TABLE XV Study Population by Gender Sex Number Female 2 Spayed female 6Male 5 Castrated male 7 Total 20

TABLE XVI Study Population by Body Weight Body Weight Number ≦10 lbs2 >10 lbs and ≦25 lbs 5 >25 lbs and ≦50 lbs 8 >50 lbs and ≦75 lbs 3 ≧75lbs 2 Total 20

On day 7 and day 14 a clinical score was again assigned to the infectedear. The results of the study are provided below in Tables XVII.

TABLE XVII Clinical Results Score Score Score Dog Day 0 Day 7 Day 14 1 61 3 2 7 4 1 3 6 2 1 4 8 8 8 5 11 2 4 6 6 6 0 7 10 5 1 8 10 4 0 9 9 3 710 10 4 1 11 6 2 2 12 10 6 1 13 6 1 0 14 9 2 0 15 10 0 0 16 10 3 3 17 95 4 18 12 6 0 19 6 2 7 20 6 1 0

A final clinical score of 2 or less was considered a treatment success.The results in Table XVII show that 65 percent of the dogs weresuccessfully treated.

Table XIX describes the culture results.

TABLE XIX Culture Results Dog Bacteria Day 0 Yeast Day 0^(b,c) BacteriaDay 14 Yeast Day 14^(b,c) 1 Negative MZ (3) Negative Negative 2 S.intermedius MZ (2) NA NA (4), β-hemolytic Streptococcus (4) 3 S.intermedius MZ (2) NA NA (4), β-hemolytic Streptococcus (4) 4

Negative

Negative

5 Negative Negative Negative Negative 6 Negative Negative NA NA 7 S.intermedius MZ (2) NA NA (4) 8 Negative Negative NA NA 9

MZ (1) Negative MZ (1) 0 S. intermedius MZ (3) NA NA (2) 11 NegativeNegative NA NA 12 S. intermedius Negative NA NA (2) 13 Negative MZ (2)NA NA 14 Negative MZ (2) NA NA 15 Negative MZ (2) NA NA 16 NegativeNegative Negative Pending 17

Negative Negative Pending 18 Negative Negative NA NA 19 S. intermediusNegative Negative Pending (4) 20 Negative Negative NA NA ^(c)MZ denotesMalasezzia pachydermatis ^(d)Scoring scale: 1 = 1 to 10 colonies; 2 = 11to 100 colonies; 3 = 101 to 1000 colonies; 4 => 1000 colonies. *Boldentries indicate treatment failures

The results in Table XVII and XIX clearly show that the pharmaceuticalcompositions of the invention are effective at treating otic microbialinfections in dogs.

5.22: Phospholipid Composition for Topical Administration

Florfenicol (10 g), betamethasone acetate (1 g), oleic acid (9.7 g), andbenzthonium chloride (1 g) were dissolved in 500 mL of propylenecarbonate and the resulting mixture heated, with stirring, to atemperature of between about 40 and 45° C. To the resulting heatedsolution was added Phospholipon®-90H (10 g) andhydroxypropylmethylcellulose (30 g) and the resulting mixture stirredfor about 10 min to provide a clear suspension. Propylene glycol wasadded to the suspension to provide a volume of about 1 L and stirringwas continued to provide a clear solution. The resulting solution wasallowed to cool slowly to room temperature to provide a gel.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosure of whichare incorporated herein by reference.

1. A pharmaceutical composition comprising: (i) a mixture of propylenecarbonate and glycerol formal in a ratio ranging from about 90:10 to10:90 containing hydroxypropylmethylcellulose dissolved therein, whereinthe hydroxypropylmethylcellulose is present in an amount ranging fromabout 0.1 to 10% by weight of the composition; (ii) a phospholipid in anamount ranging from about 0.1 to 10 percent by weight of thecomposition, and (iii) an antifungal agent, an antibacterial agent, andan anti-inflammatory agent, wherein the combination of (i), (ii), and(iii) form a gel and the pharmaceutical composition is substantiallyfree of water.
 2. The composition of claim 1, wherein the phospholipidis present in an amount ranging from about 1% to 4% by weight of thecomposition.
 3. The composition of claim 2, wherein the phospholipid hasthe structure:

wherein R₁ is —O⁻ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 4. The composition of claim 1, wherein thehydroxypropylmethylcellulose is present in an amount ranging from about2% to 4% by weight of the composition.
 5. The composition of claim 1,wherein the phospholipid is present in an amount ranging from about 1%to 4% by weight of the composition and the hydroxypropylmethylcelluloseis present in an amount ranging from about 2% to 4% by weight of thecomposition.
 6. The composition of claim 5, wherein the phospholipid hasthe structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 7. The composition of claim 5, wherein the ratioof propylene carbonate to glycerol formal ranges from about 60:40 to40:60.
 8. The composition of claim 1, wherein the ratio of propylenecarbonate to glycerol formal ranges from about 60:40 to 40:60.
 9. Apharmaceutical composition comprising: (i) a mixture of propylenecarbonate and glycerol formal containing hydroxypropylmethylcellulosedissolved therein, (ii) a phospholipid, and (iii) terbinafine or apharmaceutically acceptable salt thereof, florfenicol or apharmaceutically acceptable ester thereof, and betamethasone or apharmaceutically acceptable ester thereof; wherein the combination of(i), (ii), and (iii) form a gel and the pharmaceutical composition issubstantially free of water.
 10. The composition of claim 9, wherein thephospholipid has the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 11. The composition of claim 9, wherein thehydroxypropylmethylcellulose is present in an amount ranging from about2% to 4% by weight of the composition.
 12. The composition of claim 9,wherein the phospholipid is present in an amount ranging from about 1%to 4% by weight of the composition and the hydroxypropylmethylcelluloseis present in an amount ranging from about 2% to 4% by weight of thecomposition.
 13. The composition of claim 12, wherein the phospholipidhas the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 14. The composition of claim 9, wherein the ratioof propylene carbonate to glycerol formal ranges from about 60:40 to40:60.
 15. The composition of claim 9, wherein the terbinafine or apharmaceutically acceptable salt thereof is present in an amount rangingfrom about 1% to 3% by weight of the composition, the florfenicol or apharmaceutically acceptable ester thereof is present in an amountranging from about 1% to 3% by weight of the composition, and thebetamethasone or a pharmaceutically acceptable ester thereof is presentin an amount ranging from about 0.05% to 0.3% by weight of thecomposition.
 16. The composition of claim 15, wherein the phospholipidis present in an amount ranging from about 1% to 4% by weight of thecomposition.
 17. The composition of claim 16, wherein the phospholipidhas the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 18. The composition of claim 15, wherein thehydroxypropylmethylcellulose is present in an amount ranging from about2% to 4% by weight of the composition.
 19. The composition of claim 15,wherein the phospholipid is present in an amount ranging from about 1%to 4% by weight of the composition and the hydroxypropylmethylcelluloseis present in an amount ranging from about 2% to 4% by weight of thecomposition.
 20. The composition of claim 19, wherein the phospholipidhas the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15.
 21. The composition of claim 15, wherein theratio of propylene carbonate to glycerol formal ranges from about 60:40to 40:60.
 22. A pharmaceutical composition comprising: (i) a mixture ofpropylene carbonate and glycerol formal in a ratio ranging from about60:40 to 40:60 containing hydroxypropylmethylcellulose dissolvedtherein; (ii) a phospholipid having the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15; (iii) terbinafine or a pharmaceuticallyacceptable salt thereof; (iv) florfenicol or a pharmaceuticallyacceptable ester thereof; and (v) betamethasone or a pharmaceuticallyacceptable ester thereof, wherein: the phospholipid is present in anamount ranging from about 1% to 4% by weight of the composition; thehydroxypropylmethylcellulose is present in an amount ranging from about2% to 4% by weight of the composition; the terbinafine or apharmaceutically acceptable salt thereof is present in an amount rangingfrom about 1% to 3% by weight of the composition; the florfenicol or apharmaceutically acceptable ester thereof is present in an amountranging from about 1% to 3% by weight of the composition; thebetamethasone or a pharmaceutically acceptable ester thereof is presentin an amount ranging from about 0.05% to 0.3% by weight of thecomposition; and wherein the combination of (i), (ii), (iii), (iv), and(v) form a gel and the pharmaceutical composition is substantially freeof water.
 23. A pharmaceutical composition comprising: (i) a mixture ofpropylene carbonate and glycerol formal in a ratio ranging from about90:10 to 10:90 containing hydroxypropylmethylcellulose dissolvedtherein, wherein the hydroxypropylmethylcellulose is present in anamount ranging from about 0.1 to 10% by weight of the composition; (ii)a phospholipid in an amount ranging from about 0:1 to 10 percent byweight of the composition, and (iii) an antifungal agent, anantibacterial agent, and an anti-inflammatory agent, wherein (i), (ii),and (iii) are combined together at a temperature of about 40° C. toprovide a solution and then cooled to room temperature provide a gel,and wherein the pharmaceutical composition is substantially free ofwater.
 24. The pharmaceutical composition of claim 23, wherein theantifungal agent is terbinafine or a pharmaceutically acceptable saltthereof, the antibacterial agent is florfenicol or a pharmaceuticallyacceptable ester thereof, and the anti-inflammatory agent isbetamethasone or a pharmaceutically acceptable ester thereof.
 25. Apharmaceutical composition comprising: (i) a mixture of propylenecarbonate and glycerol formal in a ratio ranging from about 60:40 to40:60 containing hydroxypropylmethylcellulose dissolved therein; (ii) aphospholipid having the structure:

wherein R₁ is —O³¹ and R₂ and R₃ are each independently stearoyl groupsor palmitoyl groups wherein the ratio of stearoyl groups to palmitoylgroups is about 85:15; (iii) terbinafine or a pharmaceuticallyacceptable salt thereof; (iv) florfenicol or a pharmaceuticallyacceptable ester thereof; and (v) betamethasone or a pharmaceuticallyacceptable ester thereof, wherein: the phospholipid is present in anamount ranging from about 1% to 4% by weight of the composition; thehydroxypropylmethylcellulose is present in an amount ranging from about2% to 4% by weight of the composition; the terbinafine or apharmaceutically acceptable salt thereof is present in an amount rangingfrom about 1% to 3% by weight of the composition; the florfenicol or apharmaceutically acceptable ester thereof is present in an amountranging from about 1% to 3% by weight of the composition; thebetamethasone or a pharmaceutically acceptable ester thereof is presentin an amount ranging from about 0.05% to 0.3% by weight of thecomposition; and wherein (i), (ii), (iii), (iv), and (v) are combinedtogether at a temperature of about 40° C. to provide a solution and thencooled to room temperature provide a gel, and wherein the pharmaceuticalcomposition is substantially free of water.